Metallospheres and superclusters

ABSTRACT

Unimolecular micelles, generally referred to as cascade polymers, are constructed via the addition of successive layers, or tiers, of designed monomers, or building blocks, that possess a predetermined, branched superstructure consisting of connected physical matter inherently defining an internal void volume or void area within the molecular framework. Each of the branches define a flexible arm from a central core atom and terminate with a hydrodynamic reactive group. A method is described for manipulating such cascade polymers.

This is a continuation-in-part application of U.S. Ser. No. 196,292,filed Feb. 11, 1994, now abandoned, which is a divisional of U.S. Ser.No. 116,912, filed on Sep. 7, 1993, U.S. Pat. No. 4, 907,615.

TECHNICAL FIELD

The present invention relates to highly-branched molecules possessing apredetermined three-dimensional morphology, referred to as unimolecularmicelles. More specifically, the present invention relates to micelleshaving uses in areas such as radio-imaging, drug delivery, catalysis,size standards for chromatography and the like and other areas.

BACKGROUND OF THE INVENTION

Neat and orderly arrays for micellar systems have been reported,¹,2 andare structurally based on the original work of Vogtle et al.,^(3a) whodelineated "cascade" construction. The U.S. Pat. Nos. 4,435,548, issuedMar. 6, 1984; 4,507,466, issued Mar. 26, 1985; 4,558,120, issued Dec.10, 1985; 4,568,737, issued Feb. 4, 1986; 4,587,329; issued May 6, 1986;4,631,337, issued Dec. 23, 1986; 4,694,064, issued Sep. 15, 1987; and4,737,550, issued Apr. 12, 1988, all to Tomalia et al., relate tobranched polyamidoamines. The polyamidoamines include a plurality ofpendent aminoamide moieties exhibiting properties which are related tolinear polyamidoamines from which the branched polymers are derived.These compounds can be characterized as high molecular weight,highly-branched, multi-functional molecules possessing athree-dimensional morphology. Synthetic strategies employed for therealization of such "cascade polymers"^(3b) require consideration ofdiverse factors including the content of the initial core, buildingblocks, space for molecules, branching numbers, dense packing limits,and desired porosity, as well as other factors.⁴ The selection of thebuilding blocks govern the type of branching desired from the coremolecule, as well as the technology used to attach each successive layeror "tier" of the cascade polymer.

Applicants have developed a novel method of making cascade polymers,especially those providing a unimolecular micelle consisting essentiallyof alkyl carbon possessing diverse terminal functionality. Suchcompounds are disclosed in U.S. Pat. No. 5,154,853 (1992) to applicants.

Further developments of the above-described chemistry by applicants havedemonstrated that the unimolecular micellar character permits theinitial evaluation of the orderliness and chemistry within a series ofspecifically designed, spherical macromolecules due to covalently boundassemblies of internal reactive sites.⁵,6 Similar dendritic species havebeen constructed with amide,⁴,7,8 ethereal,⁹,10 phosphonium,¹¹silicone,¹² germane,¹³ and aryl,¹⁴⁻¹⁹ inner linkages andfunctionalities.

Out of all these systems, however, it has been determined that onlythree systems thus far created have the potential to undergospecifically located chemical modification within the inner lipophilicregions thereof. When there is actual space within these regions, theselipophilic regions are termed "void regions". The sum of the "voidregions" constitutes the total "void volume" of the cascade polymer. Thepresently known compounds having such inner void regions capable ofcovalent modification are the hydrocarbon-constructed cascadeintermediates possessing specifically located internal substituents orunsaturated centers, e.g., dialkylacetylenic moieties, set forth in theabove-captioned patent to applicants (U.S. Pat. No. 5,154,853), thosecompounds disclosed by Moore and Xu,¹⁹ that possess rigid polyalkynespacers, or connectors, between branching centers and are thus prone toincomplete chemical transformations, and hence asymmetry, due to stearicinteractions, and those compounds set forth in the Tomalia patents setforth above which are amino-branched compounds having short linkagesbetween branch points (thus minimizing void volume) and internalbridging trialkyl substituted nitrogen atoms possessing less than puresp³ hybridization, making internal nucleophilic substitution difficult.

Critically, applicants have found⁶ that the dialkylacetylene moieties ofthe cascade polymers set forth herein are also specifically locatedwithin accessible void regions. Applicants have shown that molecularguest probes, including diphenylhexatriene (DPH), phenol blue (PB),naphthalene, chlortetracycline (CTC), and pinacyanol chloride (PC) canbe used as micellar probes to access the infrastructure of such cascadepolymers utilizing known chemistry.²⁰⁻²⁴

Applicants' demonstrations of accessibility of void regions to chemicalmodification has led to the development of the ability to manipulateinternal moieties within the spherically symmetrical dendriticmacromolecule, after construction, to allow easy incorporation ofinternally located sensitive and/or reactive groups which otherwisewould be difficult to introduce or protect during cascade construction.Specifically, the introduction of metal and metalloid centers at theinterior of cascade infrastructures has been accomplished. Such derivedcompounds, referred to generically as metallospheres, superclusters,unimolecular Metallomicellanes and Nonmetallomicellanes,Metalloidomicellanes, derivatized Micellanes, or Micellanes, can beutilized for drug delivery of various metals and nonmetals, which arepresently difficult to deliver in pharmacologically efficacious matters.The use of carrier-metal combinations as pharmacotherapeutic agents hashad the problem of not being able to deliver sufficient metal/nonmetalto a site at a sufficiently low dose of the carrier of themetal/nonmetal per se. The present invention provides a means ofdelivering high concentrations of the metal/nonmetal moiety(ies) to asite at a relatively low dose of carrier (Micellane system).

Accessibility to void regions can be achieved by various means.Accessibility can be achieved during synthesis of tiers of themacro-molecular or can be achieved after synthesis by variousmanipulations of the molecule. It has been found that thesemanipulations of the molecule can be achieved by increasing and then,decreasing the size of the molecule. Accordingly, these size increasesand decreases can be controlled, then the present invention can relateto areas of molecular size standards, such as those used forchromatography and the like. Based on the aforementioned research,applicants have found that the specific chemical nature of the micelleconstructed in accordance of the present invention. Those allowed themto be adapted for manipulation of size to be used as a standard sizemarker. Further, the molecules can be preferentially constructed toallow for a specific size changes dependant upon branch arm flexibility,terminal groups, and the nature of the environment about the molecules.

SUMMARY OF THE INVENTION AND ADVANTAGES

In accordance with the present invention, there is provided a method ofmanipulating a unimolecular micelle in an environment wherein themicelle includes at least one core atom and arms branching from the coreatom forming an outer surface of the micelle. The method includes thesteps of reversibly changing the solubility of the outer surface of themicelle in the environment while reversibly extended the arms of themicelle to expand and contract the micelle. The present inventionfurther provides a method of preparing a unimolecular micelle by thegeneral steps of forming a core atom having a plurality of flexiblebranching arms extending therefrom and terminating each arm with ahydrodynamic reactive group.

The present invention further provides a unimolecular micelle consistingessentially of a core atom and a plurality of flexible arms extendingtherefrom, each of the arms terminating with a hydrodynamic reactivegroup.

BRIEF DESCRIPTION OF THE DRAWINGS

The file of this patent contains at least one drawing executed in color.Copies of this patent with color drawing(s) will be provided by thePatent and Trademark Office upon request and payment of necessary fee.

Other advantages of the present invention will be readily appreciated asthe same becomes better understood by reference to the followingdetailed description when considered in connection with the accompanyingdrawings wherein:

FIG. 1A shows an expanded view of the second tier of a representativeMicellane model and various guests and probe molecules;

FIG. 1B shows a contracted view of the second tier of a representativeMicellane model;

FIGS. 2A-2D show computational demonstrations of the nonbondedincorporation of various molecular probes within the representativeMicellane as illustrated in FIG. 1: wherein FIG. 2A isbuckminsterfullerene, FIG. 2B is diphenylhexatriene, FIG. 2C ischlortetracycline, and FIG. 2D is naphthalene;

FIG. 3A shows a segment of an extended view of a third tier homolog ofthe unimolecular micelle depicted in FIG. 1 with a superimposedmolecular ruler [divided into units of angstroms (Å);

FIG. 3B shows a cross-sectional view of the void volume (holes andcrevices) possessed by the homolog;

FIGS. 4A and 4C show the preparation of the first tier of a unimolecularCobaltmicelle;

FIGS. 4B and 4D show the preparation of the first tier of a unimolecularCobaltmicelle;

FIG. 4E shows the reactions of the unimolecular Cobaltmicelle witholefins;

FIGS. 5A-5B show the preparation of a unimolecular Platinomicelles,which possess multiple platinum centers within the lipophilic core;

FIGS. 6A-6B show the synthesis of a representative copper-basedunimolecular Metallomicelle;

FIGS. 7A-7B show the preparation of the first and second tierunimolecular Carboranomicelles possessing four and twelve internalortho-carborane moieties, respectively;

FIG. 8A shows the layering of tiers of the unimolecular Carboranomicellepossessing greater than four internal carborane units; and

FIG. 8B illustrates the ease of preparation of combinations of multiple(non)metallo sites feasible by the noted tier construction methodologyof these unimolecular micelles.

FIG. 9 shows building block "modules" for cascade synthesis of micellesmade in accordance with the present;

FIG. 10 shows the retrosynthetic "tree" illustrating the derivation ofalcohol, acid and amine terminated cascade polymers (micelles) made inaccordance with the present invention;

FIG. 11 is a basic LED pulse sequence, the gradient pulses being shownrepresenting the last two pulses in a train of five matched and equallyspaced pulses, phase cycling and sometimes homospoil pulses during T_(e)being used to suppress secondary echoes; and

FIG. 12 is a graph wherein the are of the major polymer peaks versus K²(Δ-δ/3 for the cascade 108-amine polymer in acidic, neutral, and basicsolutions at 298K.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a unimolecular micelle including internalvoid areas, the void areas including reactive sites capable of covalentand noncovalent bonding to guest(s). The unimolecular micelles of thepresent invention are cascade polymers which act as micelles. Suchunimolecular micelles can be generally in the form of those disclosed inU.S. Pat. No. 5,154,853 to applicants, cited above, being all alkylmolecules, or in the form of those disclosed in the Tomalia patentsdiscussed above, having a nitrogen core or branching site. Suchcompounds have pre-defined branching, depending upon the number ofsequential tier additions that are performed in accordance with theabove-cited references. The etymology of the term "Micelle," as employedin the classical or usual sense, refers to a noncovalently associatedcollection (aggregate) of many simple molecules functioning as a unithaving unique properties (e.g., aqueous solubilization of waterinsoluble materials) that are not observed with the individual moleculeswhich comprise the micelle; whereas as used herein, unimolecular micelleor micellane refers to a single macromolecule, possessing a covalentlyconstructed superstructure, that can perform the same function(s)⁶ as aclassical micelle. Additions to these terms denote the incorporation ofspecific types of metals or nonmetals within the chemically accessiblelipophilic interior of the unimolecular micelle. The term ligand ismeant to describe any site that has the ability to donate electrondensity, such as a pair of electrons to a metal or nonmetal moiety, thusforming a covalent or noncovalent bond. Most often the term is used whendiscussing metals that are bonded, or complexed, to atoms, such as N, P,O, and/or S. The term guest(s) is (are) meant to describe any metal ornonmetal (or any reasonable combination thereof) specie(s) that can beintroduced into or onto the cascade framework. The introduction can beirreversible due to the formation of covalent bonds or reversible due tothe formation of noncovalent bonds that are easily broken (e.g.,hydrogen bonds) or the reversibility may be due to lipophilic-lipophilicand hydrophilic-hydrophilic attractions.

Micelles made in accordance with the present invention can be describedas having at least one core atom, preferably a carbon atom, and armsbranching from the core atom. The terminations of the arms or withlarger branching, possibly mid-portions of the arms may fold to form anouter surface of the micelle. The surface of the micelle is exposed toimmediately surrounding environment in which the micelle is disposed.This environment will have a certain hydrodynamic character, determinedby properties such as pH, lipophilicity-hydrophilicity characteristics.

The surfaces of the micelles can be readily coated with metal ions.Mono-, di-, and trivalent metals are being possibly bonded directly orindirectly through terminal carboxyl groups or the like, similar to thedissolution of metal ions by most micellar or acidic systems.

The micelles can be characterized as having branches or arms which canbe flexible, each of the arms terminating with a hydrodynamic reactivegroup. The term "flexible" means that the arms are capable of extendingaway from and then, in reverse, folding towards the core atom.Flexibility further describes the relativeability of these arms toextend and contract relative to the core arm. Thusly, as discussedbelow, the branches or arms can be chemically altered such that the armsor branches can extend further or shorter from the core atom therebycontrolling the ability of the micelles to expand in a given environmenthaving no hydrodynamic characteristics. In combination with theflexibility of the arms or branches, the nature of the terminal groupscan also effect the expansion of the micelle in different environments.Thusly, the selection of specific hydrodynamic reactive groups caneffect the relative expansion and contraction of the hydrodynamic radiusof these molecules.

The term "hydrodynamic reactive group" refers to chemical groups whichcan be bound to the terminal ends of arms or branches which are reactivewith outer environment based on the hydrodynamic character of theenvironment. For example, groups such as alcohols, amines, carboxyls,thiols, phosphines, ammonium ions, sulfoniums ions, phosphonium ions,nitrates, sulfates, phosphates, and carboxylates, as well as other knownreactive groups can be modified depending upon the hydrodynamiccharacter of the surrounding environment. For example, hydrodynamicchanges such as pH can protonate and deprotonate carboxyls and aminesand thereby change the solubility characteristics of these reactivegroups in the environment. Increased solubility in combination withflexibility of the arms or branches of the micelle will result inexpansion of the arms and the concomitant effective increase inhydrodynamic radius of the micelle. Essentially, the molecule becomeslarger. Decreases in the solubility will likewise contract the molecule.

It has been found that with significant increases in length of branchesor arms, the arms or branches may fold into the micelle thereby notnecessarily exposing the terminal end of the arm or branch but rather, amid-section. Accordingly, hydrodynamic groups exposed in this manner canalso effect expansion and contraction of the micelle.

As discussed below, this character of the micelles made in accordance ofthe present invention provides for a wider range of uses of themicelles.

The alkylcarbons surrounded by the branched arms of the micelles definea core therewithin. The above-cited patent discloses the incorporationof nitrogen, oxygen, sulfur, or phosphorus molecules into the molecularcore. The molecules are seated within the void regions of theinfrastructure, but not chemically bound therein. It is further possibleto incorporate chirality into either the core region or on the surface,thereby creating a chiral sphere with an objectively active surfaceand/or interior possessing the ability to resolve and recognize chiralmolecules.

The above-cited patent discloses that unimolecular micelles made inaccordance with the present invention have a porosity which ispredetermined, created by the relationships of the branches, the coredefined above, and each of the quaternary areas or tertiary centers(carbon core or nitrogen branching sites, respectively) and created byeach additional tier layered thereon. The porosity of the inside corecan be changed by increasing or decreasing the distances between thequaternary or tertiary centers; that is, by changing the branch armlengths.

As discussed above, the surface character of the micelles made inaccordance with the present invention can be varied. For example, acarboxyl surface can be created, thereby rendering the micelles usefulfor detergents and surfactants, and also reactive to pH.²⁵ Changes in pHwhich increase the solubility of the surface components can expand thedendritic arms, thereby allowing accessibility to the void regions ofthe unimolecular micelle. Returning the pH to its original character canthen contract the dendritic arms, thereby once again enclosing the voidregions. This method of changing solubility of the unimolecular micellesby changing the environment in which the unimolecular micelles areretained can be used to provide accessibility to the void regions forchemical modification, as discussed in detail below.

Besides carboxyl groups, hydroxyl groups, and amines, other acidic,neutral, and/or basic functionalities can be incorporated onto thesurface or on interior dendritic arms adjacent to the void regions ofthese unimolecular micelles as set forth in U.S. Pat. No. 5,154,853. Thevoid areas of these unimolecular micelles made in accordance with thepresent invention have been characterized. The expanded and contractednature of such dendritic arms defining the micelles have also beencharacterized.

FIG. 1 shows the expanded and contracted views of the second tier ofacidic coated unimolecular micelles made in accordance with the presentinvention, as well as depicting the void regions, and, hence, the totalvoid volume, located within the cascade infrastructure. Non-bondedmolecular guests that have been shown to be incorporated include, butare not limited to, diphenylhexatriene (DPH), phenol blue (PB),naphthalene, chlortetracycline (CTC), and/or pinacyanol chloride (PC).

The sizes of the void regions have been demonstrated computationally bythe incorporation of a 9 Å C₆₀ buckminsterfullerene, as shown in FIG.2A. As shown, four such spherical guest(s) can be conveniently hostedwithin the molecule shown in FIG. 1. FIG. 2 further shows otherpreviously used probes to be docked in a partially-expanded molecule asshown in FIG. 1 to demonstrate the porosity of these unimolecularmicelles. As tier growth continues, these void areas are incorporatedand engulfed, but are not totally filled, such that construction istotally analogous to the growth of a cauliflower, a point previouslymade by de Genees to describe N-bridged dendritic species.²⁶

The third tier homolog of the unimolecular Micellanoic acid shown inFIG. 1, when viewed from an extended perspective with a depth gauge,reveals a significant void area and an extended radius very near to 40Å, as shown in FIG. 3. The cross-sectional slice of the contractedconformer exposes holes and cavities within the molecular framework,also shown in FIG. 3.

It has been previously noted in the above-cited patent of the applicantsthat benzyl protected, unimolecular Micellynoic acids (Formulas 1 and 2)can be heterogeneously and catalytically reduced to afford thecorresponding alkanols by Pd--C, ethanol, and tetrahydrofuran. Theconcomitant hydrogenation of the internal alkene moieties isstraightforward under classical conditions, suggesting branchflexibility and the accessibility of internal functionality to facilechemical modification in accordance with the present invention. Sinceapplicants have shown that there are no signs of "dense packing" at thesurface, applicants have discovered accessible reactive sites capable ofcovalent and noncovalent attachment to guests. In accordance with thepresent invention, means are provided to manipulate these moietieswithin the spherical, symmetrical, dendritic macromolecules afterconstruction. This allows for easy incorporation of internally locatedsensitive and/or reactive groups, which otherwise might be difficult tointroduce or protect during cascade polymer construction.

Such reactive sites can be mono-, bi- and/or tridentate. Examples ofmonodentate reactive sites are olefins, amines, ethers, sulfides,phosphines, esters, amides, acids, pyridines, ketones, aldehydes, iminesand halides. Examples of bidentate sites are acetylenes, pairs ofamines, (diamines), pairs of ethers (polyethers), anhydrides, imides,pairs of ketones (diketones), pairs of pyridines (bipyridines), pairs ofamides and esters, pairs of sulfides (disulfides), pairs of phosphines,pairs of halides, pairs of carbines, pairs of acetylenes (diynes), pairsof alkenes (dienes or olefins), thioethers, thioamines, thiophosphines,phosphinoamines, and phosphinoethers. An example of tridentate reactivesites is terpyridines.

The guests can be metallic or non-metallic ligands bound to at least oneof the reactive sites. Examples of incorporated metals, genericallyknown as metal complexes, are cobalt, platinum, copper, palladium,ruthenium, osmium, iron, rhodium, iridium, nickel, silver, and gold. Asdescribed below, such metals, if charged, can be bound and capturedwithin void areas of the unimolecular micelles by covalent and/orH-bonding. The chemistry of the present invention allows for capture ofsuch metal ions or clusters in a selective manner within variousselected regions of these unimolecular micelles. Thus, hybrid orunimolecular Metallomicelles can be constructed wherein known amounts ofvarious metals can be specifically incorporated into these unimolecularmicellar systems to provide desired chemical characteristics to thefinal product.

For example, cobalt can be covalently bound within the void areas duringexpansion of the unimolecular micelle and then protected therein bycontraction of the micelle, as discussed above. Such cobaltsuperclusters can be made wherein a single unimolecular micelle cancontain a plurality of dicobalt centers, only limited by the number ofreactive sites available within the dendritic arms proximate toaccessible void regions. Uses of the cobalt superclusters include themediation of specifically located carbon-carbon bond forming chemicalreactions, known as Pauson-Khand reactions.²⁷ Similar dicobalt complexesare known to undergo reaction with other alkynes and alkenes.

Alternatively, nonmetals can also be incorporated into the unimolecularmicelles to form non-metallic superclusters. Such nonmetals can beselected from the group including boron, aluminum, gallium, tin andzirconium. These include nonmetals, generally known as metalloids, whichcan be used for such applications as the formation of new carbon-carbonbonds.

It should be noted that boron is special in that it can form boronclusters via the propensity of boron atoms to form higher order species.An example of this is the cited (see Experimental Section) reaction ofdecaborane(B₁₀ H₁₄) with the alkene reactive sites.

More particularly, the preferred embodiment of the present inventionprovides a unimolecular micelle consisting essentially of a carbon coreatom and essentially all alkyl arms extending therefrom as shown asFormula 2, wherein the R groups can indicate further branching in aquaternary manner. Each quaternary group defines at least four distinctvoid regions, each of the void regions being substantially lipophilic.As shown, at least one of the void regions includes at least one of thereactive sites, as shown in Formula 2, in the form of an alkene group.The molecules can include polyalkyne groups in void regions. By knownchemistry, these alkene groups can be derivatized to variousfunctionalities which are mono- bi- and/or tridentate as discussedabove.

As discussed above, the outer surface of these unimolecular micelles canbe made either lipophilic by the addition of uncharged functionalitieson the surface of the micelle or can be hydrophilic by the incorporationof charged or more hydrophilic moieties. Such chemistry is well known inthe art.²⁸

Alternatively, the micelles can include a plurality of tiers definingthe arms. Each of the tiers includes three branches extending therefroma moiety bound to the next tier through peptide couplings. Thediscussion and examples below, discuss the synthesis of and providesexamples of compounds including the peptide couplings. It should benoted that different couplings as well other chemical modifications tothe branches or arms can effect the flexibility of the branches and armsand thereby, in combination with the nature of the terminal hydrodynamicreactive group on the arms or branches, can effect the extent to whichthe carboxyl expands and/or contracts. It should be further noted thatalthough the terminal groups effect expansion and contraction dependantupon the nature of the environment, the arm or branch modificationresulting in increased flexibility or rigidity of the arms affects theamount of contraction and expansion. For example, a unimolecular micellewith flexible alkyl branches will possess the ability to contract (orexpand) more than a unimolecular micelle constructed with more rigidbenzenoid arms, or arms containing sites of unsaturation (e.g. c═c or cc). Such incorporated rigidity can restrict expansion and contraction bylimiting the "degrees of freedom", or number of ways, that a branch canfold and bend.

The present invention further provides a method of making cascadepolymers, generally including the steps of forming a unimolecularmicelle including internal void areas having reactive sites capable ofcovalent and hydrogen bonding to guests, and after construction of themicelle, bonding guests to a reactive site in a void area. The ligand isactually contained within the void area, the micelle thereby protectingthe guest(s) from the surrounding environment. The amount of thesepolycomplexes bound within the micelles can be controlled, therebyforming metallo- and nonmetallo-clusters within the unimolecularmicelle.

The method of construction of the unimolecular micelles is step-by-stepwhich ultimately results in a fixed, controlled, predictable, andverifiable number of reactive sites (ligands) located at predeterminedinterior and exterior positions on the cascade polymer. Thus, the numberand position of metal and nonmetal species (guests) capable of beingincorporated inside, as well as outside, the macro-molecular frameworkis also fixed, controllable, and predictable. Verification of attachmentof guests to ligands is readily ascertained via standard spectroscopictechniques, particularly ¹ H and ¹³ C NMR spectroscopies. The number ofinternally incorporated species is directly related to the size andnumber of dendritic arms containing predetermined reactive sites. Thus,a first tier, four-directional, unimolecular micelle with four preciselyplaced internal reactive sites will possess four incorporated species(metals or nonmetals) at precisely located positions. A second tier,four directional, unimolecular micelle with twelve predeterminedreactive sites will contain 12 precisely attached guests after reaction,and so on. The relevant point is that the number of attached species isvery controlled at specific loci based on our method of cascadeconstruction. Examples are the hydrogenated, polyalcohol intermediatesused in the preparation of the Unimolecular Micelles set forth in U.S.Pat. No. 5,154,853 to applicants and the Boron Superclusters andCobaltomicellanes²⁹ described in the present application and exemplifiedbelow. Even if errors exist due to incomplete transformations giving useto less than pure bimolecular micelle structures, subsequent conversionto the corresponding Metallo- or Metalloid-micellane derivatives willhave catalytic activity proportional to the number of internal metalcenters.

Generally, the present invention provides a method of preparing aunimolecular micelle by forming a core atom having a plurality offlexible branching arms extending therefrom and terminating each armwith a hydrodynamic reactive group The terms "core atom", "flexiblebranching arms" and "hydrodynamic reactive group" are discussed above.What is critical, however, is that an unimolecular micelle can beprepared to function in terms of expansion and contraction in responseto its environment by preparing the unimolecular micelle in accordancewith the present invention.

More specifically, the general procedure (which is exemplified in detailin the examples closed) includes the steps of forming a first tier byamidating a tetra acid core with a branched amine moiety whereintermination of the branches are protected from the amidation underpeptide coupling conditions. The termination of the branches thendeprotected and then the first step is repeated to form additionaltiers. Finally, the branches are terminated with the hydrodynamicallyreactive group.

The terminating step more specifically includes the steps of coupling anacid terminating branch with an acetate terminated monomer to provideacetic terminated branches and then, transesterifying the acetates toform alcohol terminations. Amine terminations are formed by coupling anacid terminated branch with a carbonate terminated monomer to providecarbonate terminated branches and then treating the carbonate with acidto form amine terminations. These synthetic approaches to thepreparation of amine and alcohol terminations are exemplified in detailin the experimental section below.

The method of preparing the micelle can further include the step ofmodifying the flexibility of the branches or arms to modify the extentto which the arms will extent. For example, the incorporation ofolefinic, or unsaturated moieties, such as a cis substitutedcarbon-carbon double bond will decrease branch chain flexibility due torestricted rotation about the (c═c) carbon-carbon double bond;represented by the formula ##STR1## as wherein R= any substituent group(i.e., alkyl) but not hydrogen. This is opposed to a `trans` substituteddouble bond represented by ##STR2## Isomerization does not occur undernormal conditions: ##STR3## `Cis` to `trans` isomerization usually onlyoccurs as a result of some external stimulus such as heat and light.

The placement of such a group into the branch(es) of a unimolecularmicelle physically puts a `molecular kink` into the said branch; thusthe arm(s) with these sites of unsaturation will not be able to extendas far as they would if they had no cis double bond. If any tier of theunimolecular micelle possess at least one carbon-carbon double bond perattached monomers, then the surface of the unimolecular micelle can notphysical exteracl as far away from the center of the unimolecularmicelle than it would if it did not possess any double bonds.

Carbon-carbon double bonds can be introduced via a number of methodsthat are well known in the art. Once such method combines monomerconnectivity with carbon-carbon double bond incorporation. This is knownas a Wittig Reaction whereby the coupling of a phosphoniumylide with acarboxyl group, such as an aldehyde, produces a carbon-carbon doublebond.

The idea of incorporating "molecular kinks" into branch chains can beextended to include other groups with similar geometries, such ascomplexed bipyridines ##STR4## and phenanthrenes, ##STR5## or somethingas simple as a disubstituted benzene ##STR6## While the inclusion ofthese types of groups in cascade superstructures inhibits expansionrigidity also reduces the extent of contraction due to the loss ofconformational degrees of freedom. The more degrees of freedom that achain, or branch, has then the more conformations, it can obtain andhence the more compact it will be able to become. The less `degrees offreedom` that a branch has then the fewer conformations it can adopt andhence, it will not be able to become as compact as a chain of an equalnumber of carbons with no `kinks`. As discussed above, the unimolecularmicelle can be expanded to allow access of metal and non-metal guests orthe reactive sites, thereby providing a means of access to the complexcenter(s) within the void area after construction of the micelle. Uponattaining access to the catalytic site(s),⁵ the transient guest(s) is(are) bound to the reactive site and the micelles contracted to containand protect the transient guest(s). As discussed above, such expansionproviding accessibility to one or more of these catalytic sites can beachieved by altering the environment, such as by changing the pH²⁵ ofthe external environment solvent or medium. Additionally, theseunimolecular micelles having a surface which is more soluble inlipophilic solvents can be transferred to a common organic solvent, suchas CH₂ Cl₂,CHCl₃, C₆ H₆, thereby expanding these lipophilic micellesallowing accessibility. The micelles then are returned to a morehydrophilic solvent causing contraction, due to an inability of thesolvent to solvate the surface.³⁰ This has been demonstrated onclassical polymers with organic solvents such as tetrahydrofuran, whichcauses polymer swelling.

In view of the above, the present invention provides a method ofmanipulating the unimolecular micelles in an environment by reversiblychanging the solubility of the outer surface of the micelle in theenvironment while reversibly extending the arms of the micelle to expandand contract the micelle. Generally, this can be done by changing theenvironment to increase the solubility of the outer surface of themicelle in that environment. Specifically, as discussed above, this canbe done by either changing the pH of the environment or thehydrolipophilic properties of the environment or other properties knownin the art. Thusly, the present invention provides a method forreversibly changing the hydrodynamic radius of the micelle.

By changing the hydrodynamic radius of the micelle, the presentinvention provides for uses not necessarily related to inclusioning ofguests in void areas of the micelle. For example, the experimentalevidence below demonstrates that the micelles made in accordance withthe present invention can be expanded to precisely known outer radii.Thusly, the present invention can be utilized as size standards forvarious molecular (i.e. sieving, chromatographic separationsstandardizing) and the like processes. The sizing functionality of themicelles also allow for precise engineering for a particular environmentof the size of the micelles to allow for passage or filtration of themicelles as desired. This can be useful in industrial applications aswell as biological applications.

The ability of the present invention to expand and contract incombination with the ability of the unimolecular micelles inclusion ofvarious guest(s), such as metals, drugs, or the like, and then expand ina certain environment to release the guest(s) provides a great utilityfor the present invention. The micelles can be engineered so as toexpand in a particular environment, whether it be a basic environment,or an acidic environment, a hydrophilic environment, etc., so as to beloaded with a guest in that environment. The micelles can then beremoved from the environment, thereby trapping the guest therein, asdescribed above and demonstrated in the example section below. This canbe designed with a target in mind wherein the target has a localenvironment which would also caused expansion of micelles. In otherwords, if the micelles expand in an acidic environment and a target issurrounded by a pH neutral environment or a basic environment whereinthe micelles remain contracted (thereby containing the guest) when themicelles reach the target having the acidic environment, the micelleswill release the guest at the environment. Hence, the unimolecularmicelles made in accordance with the present invention can be used acarrier to carry a guest through a system and release the guest at thetarget having the known local environment. This method of guest deliverycan have industrial as well as biological applications. The datapresented in the example section demonstrate this utility by showingthat guest(s) can be included and released and further show thatunimolecular micelles can be engineered to expand, include guest(s), andcontract in various environments depending upon the terminal moieties onthe arms or branches of the micelles.

The target for release of the guest molecules for the unimolecularmicelles may be located in a circulating system wherein the micelles mayhave a single pass by or through the target or multiple passes throughthe circulating system. If the micelles are sized to remain in thecirculating system for more than one pass, then the micelles can bedelivered to the circulating system and release the guest molecules fromthe micelles at the target each time the micelles circulate into thehydrodynamic environment of the target. Thusly, in an industrial device,where a certain component of the device may be in a hydrodynamicenvironment different from the remainder of the circulating system, themicelles can be used to include guest molecules to be delivered to thetarget site wherein the micelles maintain there contracted state therebycontaining the guest molecules throughout the circulating system. If thetarget site has a hydrodynamic environment in which the micelles willexpand and the release the guest molecules, the micelles will bedelivered to the target site by the circulating system and release atleast some of the guest molecules at the target site. As the micellesare moved from the target site by the circulating system, they willcontinue to contain the remainder of the guest molecules until thecirculating system returns the micelles back to the target site for moreor continued release. Thusly, the unimolecular micelles of the presentinvention can be used as a delivery system in a circulating system forcontinued targeted release of guest molecules at a specific site.Thusly, molecules such as lubricants, disenfectants, or the like oractive molecules such as catalysts or the like can be delivered tospecific sites.

The unimolecular micelles of the present invention can include armshaving alkene moieties. The alkene moieties can be treated with ametallocarbonyl in an aprotic solvent, the metallo addition beingcomplexed to the internal ligand site(s).

More specifically, the metallo moiety can be selected from the groupincluding, but not limited to, cobalt, platinum, copper, palladium,ruthenium, osmium, iron, rhodium, iridium, nickel, silver, and gold.

The aprotic solvent can be selected from, but is not limited to, thegroup including CH₂ Cl₂, HCCl₃, CCl₄, R--O--R' wherein R and R' areselected from the group consisting of aralkyl and aryl groups, C₆ H₆ andCH₃ C₆ H₅.

The unimolecular micelles of the present invention can also includepolyalkyne moieties. These polyalkyne moieties can have bonded thereto azero-valent metal under reductive conditions and in the presence of aphosphine donor to the alkene moieties. The phosphine is thermolysed togenerate the zero-valent metal trapped within the void area of theunimolecular micelle.

A further alternative is for the micelle to include arms havingbidentate diamino chelate ligands. To produce these compounds, thebonding step discussed above consists of chelating divalent copper tothe ligand. Specifically, the bidentate is formed by alkylating achloro-terminated monomer of the formula: ##STR7## wherein R=CH₂ OR',CO₂ R", CN, and CH₂ NR₂ '", R'=Me, CH₂ C₆ H₅ ; (R"=Me, Et, pr, bu(t),CH₂ Aryl and R'"=H, alkyl, aryl, and alkynyl with (2,3, or4-lithiomethyl-2', 3' or 4'-methyl) bipyridine to form the bidentatediamino of the formula selected from the group consisting of: ##STR8##

These steps can be followed by the subsequent steps of the lithiating ofterminal methyl groups and adding further polyhalides to form furtherinternal bi- or tridentate loci in void areas of the unimolecularmicelle.

A further alternative is wherein the unimolecular micelle includes armshaving polyalkyne moieties, the bonding step discussed above beingfurther defined as treating the alkene moiety with a acetonitrileactivated decarborane moiety.

In accordance with the above methods, bidentate diamino chelate ligandof the formula: ##STR9## can be made wherein R=H, alkyl, or CH₂ OR'"where R'"=CH₃, CH₂ C₆ H₅ and R'=CO₂ R", CH₂ OH, CH₂ NH₂, CN or CH₂ Xwherein X is a halogen, OMs (OSO₂ CH₃) or OTs (OSO₂ C₆ H₄ CH₃).

The following examples demonstrate the ability of the present inventionto provide incorporation into unimolecular micelles of metal andnonmetal centers.

EXAMPLE SECTION A. Complexes With Cobalt General Procedure for thePreparation of Cobalt-based Metallomicellanes.12-Cascade:methane[4]:(5,6-hexacarbonyldicobalt)nonylidyne:(2-oxapentyl)benzene

First generation Cobaltomicellane

A solution of CH₂ Cl₂ (10 mL), tetraalkyne-dodecabenzyl ether {12Cascade:methane[4]: (5,6-yn) nonylidyne: (2-oxapentyl)benzene(0.5 g) andoctacarbonyldicobalt (0.30 g, 0.89 mmol) was stirred for 12 hours undera N₂ atmosphere at 0° C. The solvent was removed in vacuo and theresidue was subjected to non-aqueous reverse phase chromatography (C₆H₆) to afford (88%) the octacobaltdodecabenzyl ether as a viscous redoil: ¹³ C NMR δ22.8 (CH₂ CH₂ O), 25.6 [Co₂ (CO)₆ C₂ CH₂ CH₂ ], 32.6 (CH₂CH₂ CH₂ O), 34.0 [Co₂ (CO)₆ C₂ CH₂ ], 36.4 [C₄°, Co₂ (CO)₆ C₂ CH₂ CH₂CH₂ ], 71.2 (CH₂ OCH₂ C₆ H₅), 72.8 (OCH₂ C₆ H₅), 127.3, 127.4, 128.3,138.6 (C₆ H₅), 201.0 (CO); ¹ H NMR δ0.60-2.70 [br m, (CH₂)₃ Co₂ (CO)₆ C₂(CH₂)₃ C{CH₂ CH₂ }₃, 96H], 3.40 (br s, CH₂ OCH₂ C₆ H₅, 24H), 4.46 (br s,CH₂ C₆ H₅, 24H), 7.30 (br s, C₆ H₅, 60H); IR (neat) v=3075, 2940, 2870,2085, 2044, 2015, 1280, 1100, 745 cm⁻¹

36-Cascade:methane[4]:nonylidyne:(5,6-hexacarbonyldicobalt)nonylidyne:(2-oxapyntyl)benzene

Second generation Cobaltomicellane ¹³ C NMR δ22.8 (CH₂ CH₂ O), 23.5 [CH₂(CH₂)₄ CH₂ ] 29.7 [(CH₂)₃ CH₂ CH₂ (CH₂)₃ ], 25.7 [Co₂ (CO)₆ C₂ CH₂ CH₂], 32.6 (CH₂ CH₂ CH₂ O), 34.0 [Co₂ (CO)₆ C₂ CH₂ ], 36.4 [C₄°, Co₂ (CO)₆C₂ CH₂ CH₂ CH₂ ]36.7 [CH₂ (CH₂)₆ CH₂ ]71.2 (CH₂ OCH₂ C₆ H₅), 72.8 (OCH₂C₆ H₅), 127.3, 127.4, 128.3 138.6 (C₆ H₅), 202.0 (CO); ¹ H NMRδ0.60-2.70 [br m, (CH₂)₈, (CH₂)₃ Co₂ (CO)₆ C₂ (CH₂)₃ C{CH₂ CH₂ }₃,356H], 3.42 (br s, CH₂ OCH₂ C₆ H₅,72H), 4.46 (br s, CH₂ C₆ H₅, 72H),7.30 (br s, C₆ H₅, 180H); IR (neat) v=3075, 2940, 2870, 2085, 2044,2015, 1280, 1100, 745 cm⁻¹

The reactivity within the lipophilic core of these unimolecular micelleswas conducted via treatment of the internal alkene moieties of Formulas1 and 2 with Co₂ (CO)₈ ³¹ in an aprotic solvent such as CH₂ Cl₂, shownin FIG. 4. Dicobaltoctacarbonyl is well known to form additionalcomplexes to acetylenes and has been successfully employed for theirprotection.³¹ These resultant dicobalt complexed alkynes act not only asprotecting groups but also promote ene-yne cyclopentenone cyclization,³²thus affording entry to a novel series of carbocyclic substitutedmicelles via chemical modification of their internal lipophilic region.Substituents attached to the guest alkene allow precise placement ofdiverse functionality within one or more of the micellar void volumeregions.

The information of functionalized terminal alkene guests is envisionedvia the formal 2+2+1 cyclization. Thus, treatment of cobaltsuperclusters Formulas 3 or 4 (FIG. 4) with 4-vinylpyridine or methylacrylate should afford Formulas 5a,b or 7a,b (FIG. 4). Benefits of thetransformation include the incorporation of α,β-unsaturated carbonylmoieties and precisely anchored reagents which can be used to ascertainan accurate "depth of reagent" inside the inherent cavities in thesederivatized unimolecular micelles. Insight also is afforded into theregiochemistry of the cyclizations.^(34a),35 The nature of the reagentsenvironment (i.e., hydrophobicity, lipophilicity, mobility, density,etc.) can then be related to that observed for classical micelles.²

Isolation and purification of the Co₂ (CO)₆ intermediates have beenreported³² generally not to be required prior to ene-yne cyclization dueto high conversions. Treatment of the tetraalkyne Micellane (Formula 1)with dicobaltoctacarbonyl affords (≈100%) the deep red, viscousdicobalthexacarbonyl adduct (Formula 3). Formation was evidenced by theappearance of ¹³ C NMR resonances at 200.3 (C.tbd.O) and 99.6 ppm [C₂(CO₂ (CO)₆ ], as well as the disappearance of signals at 80.1 and 19.3ppm attributed to the C.tbd.C and α-CH₂ precursor moieties,respectively. Further support was provided by the symmetry of the ¹³ CNMR spectrum and severe broadening of the ¹ H NMR spectrum, and an IRabsorption at 2000 cm⁻¹.

4-Dicobalt clusters were attached at four discrete loci at a distance nogreater than 6.4 Å³⁶ from the core atom. Similar ¹ H and ¹³ C NMRspectral signals are observed when the dodecaalkyne derivatizedMicellane (Formula 2) is treated with Co₂ (CO)₈ to afford thedodecadicobalt supercluster (Formula 4). As each tier is added, thenumber of internal alkene sites increases (4→12→36→108 . . . ), thusplacing each set of alkene centers at a discrete distance from the core(6.4, 17.3, 28.4, and 37.4 Å, respectively); each center available forsubsequent complex formation. Since the dicobalt clusters are protectinggroups for the alkene moiety, the initial 4 clusters at 6.4 Åweremaintained during construction of the next tier. Addition of twelveequivalents of Co₂ (CO)₈ will afford a micellar species with 16-dicobaltclusters. This procedures can be repeated with added tiers affording 52(4+12+36)- or 160 (4+12+36+108)dicobalt cluster centers within thehydrophilic surface coat.

One is not limited to a single metal source. Each tier can incorporatedifferent metal ions or clusters. Thus, the initial 4-dicobalt clustersat tier 1 can be covered by 12-Pt(0) (next section) sites at tier two.Since each tier is constructed independently of the preceding layer,numerous possibilities are conceivable and attainable, provided thechemical stability is maintained during the attachment of subsequenttiers.

B. Complexes with Platinum

The incorporation of moieties into dendritic "void regions" includes theincorporation of zero-valent metals, such as Pt(0).³⁷ Thus, theutilization of Pt(0), generated from K₂ PtCl₄ under reductive conditions(NaBH_(4') EtOH) in the presence of R₃ P (R=alkyl, aryl or aralkyl)leads to platinacycles (Formulas 7 or 8), depending on the size andnumber of unsaturated centers, as noted above, of the unimolecularmicelle (FIG. 5). As the tiers are added, the cavities are eventuallysealed (onset of dense packing). However, they are still porous due tothe facile molecular motion of the surface functionality at ambient andabove temperatures. Thus, thermolysis of the platinocycles within themetallospheres liberates irreversibly the volatile R₃ P ligands togenerate Pt(0)³⁷ metal atoms trapped within the inner lipophilicmicroenvironment.

Examination of these Metallomicelles can be expanded to include thepreparation of poly-Pd(0) adducts. Although these palladiocycles areless stable towards external parameters, such as oxidation and heat,they exhibit chemistry similar to their platinum counterparts.³¹

The generation and migration of metal(0) species within inerthydrocarbon pockets afford small, e.g. Pt(0)_(n') clusters. The mobilitywithin a single pocket affords at least four similar Pt(0)_(n) clustercenters, but if inter-region migration occurs, a "colloidal transitionmetal cluster"³⁸ is possible. Other platinum family metals can beincorporated via similar technology.³⁸ If intracavity migration occurs,the cluster is limited to a fixed number of metal atoms, and eachcluster and symmetry is retained; whereas, if intercavity metal atommigration occurs, cluster size is variable and molecular dissymmetry ofthe metallomicelle results.

C. Complexes with Copper

Copper-based "metallomicelles" have been shown by Menger tosignificantly enhance the rate of phosphodiester hydrolysis [e.g., nerveagent GD; (RO)₂ POF] by as much as 10⁶ due to increased electrophilicitycreated by constrained metal centers.² Introduction into the cascade ofa suitable Cu²⁺ ligand leads to copper-based metallospheres that possessthis capability.

Copper-based metallomicelles are constructed from novel cascade buildingblocks that incorporate bidentate diamino ligands. Alkylation of thechloro-terminated monomer[4-(3-chloropropyl)-4-(3-benzyloxypropyl)-1,7-dibenzyloxyheptane]⁵ with(2-lithiomethyl-2'-methyl)bipyridine³⁹ easily affords a rigid buildingblock (Formula 10) with the requisite chelate site. Since selectivemetallation has been demonstrated,⁴⁰,41,42 subsequent lithiation of theremaining terminal methyl group and addition of a poly-halide core⁵(e.g., 4, 12, or 36 terminal halides, etc.) provides a series of cascadeinfrastructures (Formula 11) possessing these internal bidentate loci(FIG. 6). Although copper inclusion is shown, this technique can beapplied to many other metal ions.⁴³

D. Boron Clusters General Procedure for the Preparation of BoronSuperclusters12-Cascade:methane[4]:5,6-(1,2-dicarba-closo-dodecarborane)nonylidyne:(2-oxapentyl)benzene

First generation boron supercluster

A solution of acetonitrile (1.0 mL) and excess decaborane (0.3 g, 2.4mmol) was stirred at 25° C., under a N₂ atmosphere, for 30 min.Subsequently, a mixture of toluene (7.0 mL) and thetetraalkyne-dodecabenzyl ether{12-Cascade:methane[4]:(5,6-yn)nonylidyne:(2-oxapentyl)benzene} (0.5 g,0.22 mmol) was added. After refluxing for 24 hours, MeOH (5.0 mL) and10% HCI (1.5 mL) were added and reflux was continued for another 12hours. Upon cooling to 25° C., the solvent was removed in vacuo, CH₂ Cl₂(50 mL) was added and subsequently washed with 10% Na₂ CO₃ (2×50 mL) andsaturated brine (2×50 mL), and dried (NaSO₄). Concentration in vacuofollowed by non-aqueous reverse phase chromatography (10:0.1 v/v C₆H_(6:) EtOAc) afforded (92%) the puretetra-1,2-dicarba-closo-dodecarborane supercluster: ¹³ C NMR δ23.5 (B₁₀H₁₀ C₂ CH₂ CH₂ CH₂ CH₂ O), 29.6 (B₁₀ H₁₀ C₂ CH₂), 32.4 (CH₂ CH₂ CH₂ O),36.5 (C₄°,B₁₀ H₁₀ C₂ CH₂ CH₂ CH₂), 71.2 (CH₂ O), 72.8 (OCH₂ C₆ H₅),127.3, 127.4, 128.3, 138.6 (C₆ H₅); ¹ H NMR δ0.85-2.10 [m, (CH₂)₃ B₁₀H₁₀ C₂ (CH₂)₃ C{CH₂ CH₂ }₃, 136H], 3.40 (br s, CH₂ O, 26H), 4.46 (br s,OCH₂ C₆ H₅,24H), 7.30 (br s, C₆ H₅, 60H); .sup. 11 B NMR (¹ H decoupledδ-19.6 (s, B₃,6), 0.5 (m, B₄,5,7,11), 23.6 (s, B₈,10), 35.6 (br s,B₉,12); ¹¹ B NMR (¹ H coupled) δ-19.6 (d, B₃,6, J=145.2Hz), 0.5 (m,B₄,5,7,11), 23.6 (d, B₈,10, J=119.5Hz), 35.6 (br s, B₉,12); IR (neat) v3080, 3030, 2920, 2860, 2575, 1100, 745, 700 cm⁻¹.

36-Cascade: methane[4]:nonylidyne:5,6-(1,2-dicarba-closo-dodecarborane)nonylidyne:(2-oxapyntyl)benzene

Second generation boron supercluster

The experimental procedure is the same as that described for the firstgeneration, 12-Cascade, boron supercluster. ¹³ C NMR δ22.5 [C(CH₂ CH₂)₄^(int) ], 23.5[C(CH₂ CH₂)]₄ ^(ext),CH₂ CH₂ O, 29.0 [C(CH₂ CH₂ CH₂ CH₂)₄^(int) ], 29.5 (B₁₀ H₁₀ C₂ CH₂), 31.5 [C(CH₂ CH₂ CH₂)₄ ^(int) ], 32.6(CH₂ CH₂ CH₂ O), 36.6 [m, C₄°,C₄° (CH₂)₄ ], 71.3 (CH₂ O), 72.8 (OCH₂ C₆H₅), 127.3, 127.4, 128.3, 138.6 (C₆ H₅); ¹ H NMR δ0.70-2.15 [br s,(CH₂)₈ ^(int), (CH₂)₃ B₁₀ H₁₀ C₂ (CH₂)₃ C{CH₂ CH₂ }₃ ^(ext), 372H]3.41(br s, CH₂ O, 72H), 4.47 (br s, OCH₂ C₆ H₅, 70H), 7.30 (br s, C₆ H₅);180H); ¹¹ B NMR (¹ H decoupled) δ-19.6 (s, B₃,6), 0.5(m,B₄,5,7,11),23.6(s,B₈,10), 35.6 (br s, B₉,12); IR(neat) v=3080, 3030, 2920, 2860,2575, 1100, 745, 700 cm⁻¹

Synthesis of water-soluble boron clusters to be used in cancertreatment, specifically, boron neutron capture therapy, has been thesubject of recent investigations.⁴⁴ Localization of high concentrationsof boron, provided by 1,2-dicarba-closo-dodecarboranes (o-carboranes),at tumor sites and subsequent neutron activation results in the decay of¹⁰ B (20% natural abundance) to an α-particle and ⁷ Li which interfereswith cancer cell replication. Aqueous solubilization has thus far reliedon transformation of B₁₀ H₁₀ closo-structures to ionic [B₉ H₁₀ ]⁻nido-structure,^(44a),b or attachment of a single o-closo-carborane to asmall, water-soluble delivery molecule.^(44c) These methods lack theadvantage of delivery of a maximum amount of boron with a minimum dose.Water-soluble polycarborane cascades would circumvent this limitation.

Initial investigations of cascade-based, boron superclusters havefocused on the successful synthesis of the tetrakis(o-carborane)⁴⁵(Formula 11) via treatment of the polyalkyne monomer Formula 1 (FIG. 7)with acetonitrile activated decaborane. Similarly, treatment of thedodecaalkyne cascade (Formula 2) with decaborane yielded thedodeca-o-carborane (Formula 12). Evidence for the formation of Formulas11 and 12 included the disappearance of ¹³ C NMR peaks at 80.1 (C.tbd.C)and 19.3 ppm (CH₂ C.tbd.C) and the appearance of a peak at 29.5 ppm (CH₂C₂ B₁₀ H₁₀). The ¹ H NMR spectrum exhibited a sharp, intense peak at2.51 ppm (B₁₀ H₁₀) postulated to arise by the rapid rate of quadruplerelaxation in boron.⁴⁶ The exceptional stability of carboranes isemployed to obtain supercluster water-solubility. Thus, hydrogenolysisof the benzyl ether moieties (Pd--C) followed by oxidation of theterminal alcohols (CrO_(3') H₂ SO₄) to carboxylic acid groups affordsthe requisite solubilizing terminal moieties after treatment with base.Third and fourth tier cascade intermediates, when subjected to the sameprocedures, would afford water-soluble superclusters possessing 36 and108 o-carborane clusters, respectively.

Alternatively, carborane superclusters are prepared wherein each tier orlayer of monomer added is treated with decaborane to provide a maximumamount of o-carborane groups within the internal Micellane environment.Thus, second and third generation cascades (Formulas 13 and 14) possess16 and 52 o-carborane moieties, respectively (FIG. 8).

E. Characterization

Proof of structure is ascertained by NMR spectroscopy.⁵ The inclusion ofthese anisotropic centers within the lyophilic core facilitates NMRstudies of included guest(s) moieties and their immediate environment.These data afford insight to the degree of inclusion (penetration)within spherical (Hartley model) micelles. Electron microscopy is usedto visually demonstrate the size and shape of the product(s). Sincethese spherical medio/macromolecules swell and contract under varyingsolvent and pH conditions,²⁵ controlled access to these inner metal lociis achieved under very rigid conditions. The introduction of appropriateguests to these potentially catalytic sites is realized in an aqueousenvironment, since non-porotic guests favor these lipophilic innerregions. The synthesis, characterization, and chemistry of water-solubleunimolecular metallomicelles and metalloidomicelles possessing innerlipophilic pockets containing metal catalytic sites are hereindisclosed.

The above examples demonstrate the ability of the present invention tofill void regions by chemical means within dendritic macromolecules. Asadditional layers are added, constraint will then be imposed at theonset of surface "dense packing" in these dendritic systems. Thechemistry of the present invention utilizes inter- and intra-molecularhost-guest interactions, as well as chemical transformations at apre-determined depth within the specific micellar environment.Accordingly, the present invention provides means of utilizing not onlythe exterior of the micelle for interaction with this environment, butalso the lipophilic interior of the unimolecular micelle. Thesemodifications allow for reaction of the micelles in a dramatic fashionwith the surrounding environment. The surrounding environment,physiologically, can be drastically modified by such aninter-relationship. Such modification can be medicinal in nature, themicelles providing a pharmacological delivery mechanism.

F. Demonstration of pH Dependence of Hydrodynamic Ratio of Micelles

The following examples demonstrate the synthesis of unimolecularmicelles having flexible branching arms and terminating each arm with ahydrodynamic reactive group, such as amine or alcohol. The datademonstrate a pronounced pH dependence. Accordingly, the followingexperiments demonstrate the method of synthesis of the inventivemicelles as well as the expansion characteristics in changingenvironments.

G. Synthetic Aspects

As shown in FIG. 9, while tetraacid 1 and amines 2 and 3 were readilyavailable, the development of amine 4 enabled pursuit of the strategyillustrated by the retrosynthetic tree, shown in FIG. 10. This divergentstrategy, which involved attachment of a "module" (i.e., branched amine)to the appropriate acid terminated dendrimer gives facile access tonanoscale spheres with porous infrastructures.

Amine 4 was prepared from the branched trinitrile 5,⁴⁷, as shown inScheme 1. ##STR10##

Borane reduction of 5 gave (82%) trimine 6 as indicated by a loss of thenitrile (¹³ C NMR) resonance at 119.3 ppm, the appearance of a peak atδ42.5 (CH₂ NH₂) and a (¹ H NMR) triplet (CH₂ NH₂, J=6.0Hz, 6H) at 2.65ppm. Treatment of triamine 6 with di-tert-butyl dicarbonate and Et₃ N inrefluxing MeOH gave (87%), after workup and purification via column(SiO₂)chromatography, tricarbamate 7. The ¹³ C NMR spectrum of 7possesses the expected seven peaks; signals at 28.3 (CH₃), 79.1 (CMe³),and 156.0 (C═O) ppm correspond to the tert-butoxycarbonyl (Boc)moieties. Catalytic reduction (T-Raney Ni, H₂, 55 psi, 65° C., 12 hours)of 7 gave (92%) amine 4; reduction was confirmed by a shirt (¹³ C NMR)of the quaternary carbon resonance from 94.2 to 52.8 ppm.

The preparations of dodeca-tert-butylester 10, dodecaacid 11,36-tert-butylester 16, 36-acid 17, 108-tert-butylester 22, and 108-acid23 have been described;⁴⁸ complete synthetic details are given in theexperimental synthesis section below. syntheses of the first generationdodeca- alcohol 9, acid 11, and amine 13 are depicted in Scheme 2.##STR11##

In each case, the tetraacid core 1 was aminated with the branched aminebuilding block via standard dicyclohexylcarbodiimdie⁴⁹,50/1-hydroxybenzotriazole⁵¹ (DCC/1-HBT) peptide coupling conditions,before facile removal of the protecting group. The second (Z=36) andthird (Z=108) generation alcohol terminated cascades ("arborols") andamine terminated cascades were similarly prepared from dodecaacid 11Scheme 3) and the second tier 36-acid (not shown), respectively.##STR12##

The first three generations of the alcohol terminated cascade polyamideswere prepared having the general family nameZ-Cascade:methane[4]:(3-oxo-6-oxa-2-azaheptylidyne):(3-oxo-2-azapentylidyne)^(G-1):propanol. Coupling of tetraacid 1 with amine 3 via treatment withDCC/1-HBT in DMF at 25° C. provided (47%) dodecaacetate 8, which wascharacterized by eleven (¹³ C NMR) resonances. Two (¹ H NMR) triplets at2.37 (CH₂ CONH) and 3.63 (OCH₂) ppm and a singlet at 3.31 (⁴° C_(Core)CH₂ O) ppm, which were attributed to the core of 8, gave properintegration relative to each other and to each of the resonances of thetwelve exterior branches. Base-catalyzed transesterification of 8,followed by purification via dialysis, gave (36%) dodecaalcohol 9, asevidenced by the loss of the (¹ H and ¹³ C) NMR resonances and IRstretches attributed to the acetyl moieties. The relatively low yieldsfor these materials are probably due to losses during dialysis. Theformula weights of these materials are close to the molecular weightcut-off (MWCO) rating of the dialysis membrane. Coupling amine 4 totetraacid 1 gave (56%) dodecaurethane 12, which was hydrolyzed in formicacid (95%) at 25° C. The formate salt was treated with dilute aqueousHCl and dialyzed to provide (37%) dodecaamine 13 as its hydrochloridesalt. Again, the relatively low yields for these materials are probablydue to losses during dialysis. The formula weights of these materialsare close to the molecular weight cut-off (MWCO) rating of the dialysismembrane. The ¹³ C NMR spectrum exhibited the expected nine resonances.The second generation 36-carbamate 18 and third generation 108-carbamate24 were similarly prepared and deprotected to give 36-amine 19 and108-amine 25, respectively. The ¹ H NMR spectra (D₂ O) of 19 and 25contained core methylene signals at 2.38, 3.21, and 3.54 ppm that gaveproper integration relative to each other and to resonances at 1.73 and2.16 ppm, attributed to the interior methylenes, and at 1.44, 1.58, and2.82, corresponding to the methylene groups of the exterior branches.

H. Pulsed Field Gradient NMR Studies

The following experiments test the hydrodynamic effects of theenvironment on the expansion and contraction of the micelles. D₂ Osolutions containing an alcohol or amine terminated cascade polymer wereexamined by means of Diffusion Ordered 2D-NMR Spectroscopy (DOSY).⁵²This method, which makes use of pulsed field gradient NMR (PFG-NMR),displays chemical shifts in one direction and diffusion coefficients inthe other. As previously reported for the acid terminated polymer, thediffusion dimension revealed only the HOD peak and a single polymerpeak. Therefore, data acquisition and analysis was focussed on thepolymer peaks. In principal, the complete DOSY experiment requires nomore time than a PFG-NMR experiment for one peak; however, the nuclearrelaxation time T₁, is much longer for HOD than for the polymers and therepetition time required for acquisition of the complete DOSY data setis determined by the longest T₁ in the sample. Thus, to obtain themaximum signal to noise ratio, the experimental parameters wereoptimized for the polymer peaks at the expense of the uninteresting HODsignal.

All experiments were performed with the Longitudinal-Eddy-Current Delaypulse sequence (LED) shown in FIG. 11 to minimize distortions resultingfrom eddy currents and the effects of J-modulation⁵³. An activelyshielded gradient coil set was also used to minimize pulse induced eddycurrents.⁵⁴ The DOSY data sets were acquired and analyzed as previouslydescribed.⁵² Diffusion coefficients were obtained for each generation ofthe water soluble alcohol and amine terminated polyamines at ca. 1 mMconcentration by using only the integral A of the major polymer peaks. Atypical 1H 250 MHz data set is shown in FIG. 12 for the 108-aminecascade polymer. The integrals of the polymer peaks were fit bynonlinear regression to the Stejskal-Tanner equation.⁵⁵

    A=A.sub.o exp[-K.sup.2 Δ-δ3)D]                 (1)

with A_(o) and the tracer diffusion coefficient D as free parameters. InEquation 1,K=γgδ, where γ is the magnetogyric ratio, g and δ are theamplitude and duration of the gradient pulses, respectively, and Δ isthe diffusion time (i.e., the time between the leading edges of thegradient pulses). In these experiments Δ-100.0 ms and δ=1.00 ms. Also,the rf pulse pair separation was τ=1.60 ms and the eddy current delayperiod was T_(e) =20.0 or 25.0 ms. Effective hydrodynamic radii werecalculated from measured D values with the Stokes-Einstein equation,R_(H) =k_(B) T/(D6πη), where k_(B) is the Boltzmann constant, T is theabsolute temperature, and η=1.098 cp is the viscosity of D₂ O at 298K.⁵⁶

The measured diffusion coefficients and calculated hydrodynamic radiifor the alcohol and amine-terminated cascade polyamides are listed inTable 1.

                                      TABLE 1                                     __________________________________________________________________________    Observed diffusion coefficients and calculated hydrodynamic radii for the     four-directional cascade polymers.                                                  Number of                                                               Generation                                                                          Terminal                                                                            Terminal                                                                             Formula                                                                            [Cascade]                                                                          D (cm.sup.2 s.sup.-1)/Hydrodynamic Radius                                     (Å)                                          (G)   Groups (Z)                                                                          Functionality                                                                        Weight                                                                             (mM) Acidic pH                                                                            Neutral pH                                                                           Basic pH                           __________________________________________________________________________    1      12   --CO.sub.2 H.sup.a                                                                   1,341                                                                              1.00 2.41 × 10.sup.-6                                                               1.62 × 10.sup.-6                                                               1.68 × 10.sup.-6                         10                8.24  12.3   11.8                                           --CH.sub.2 OH.sup.b                                                                  1,174                                                                              1.00 2.30 × 10.sup.-6                                                               2.33 × 10.sup.-6                                                               2.35 × 10.sup.-6                         9                 8.64   8.53   8.46                                          --CH.sub.2 NH.sub.2.sup.c                                                            1,162                                                                              1.00 1.68 × 10.sup.-6                                                               1.75 × 10.sup.-6                                                               1.92 × 10.sup.-6                         13               11.8   11.4   10.3                               2      36   --CO.sub.2 H.sup.a                                                                   4,092                                                                              1.00 1.74 × 10.sup.-6                                                               1.15 × 10.sup.-6                                                               1.26 × 10.sup.-6                         17               11.4   17.3   15.8                                           --CH.sub.2 OH.sup.b                                                                  3,589                                                                              1.00 1.57 × 10.sup.-6                                                               1.56 × 10.sup.-6                                                               1.60 × 10.sup.-6                         15               12.7   12.7   12.4                                           --CH.sub.2 NH.sub.2.sup.c                                                            3,553                                                                              1.00 1.09 × 10.sup.-6                                                               1.20 × 10.sup.-6                                                               1.44 × 10.sup.-6                         19               18.2   16.6   13.8                               3     108   --CO.sub.2 H.sup.a                                                                   12,345                                                                             1.00 1.15 × 10.sup.-6                                                               8.32 × 10.sup.-7                                                               9.09 × 10.sup.-7                         23               17.3   23.9   21.9                                           --CH.sub.2 OH.sup.b                                                                  10,834                                                                             0.50 1.30 × 10.sup.-6                                                               1.28 × 10.sup.-7                                                               1.28 × 10.sup.-7                         21               15.3   15.5   15.5                                           --CH.sub.2 NH.sub.2.sup.c                                                            10,728                                                                             1.00 7.90 × 10.sup.-7                                                               8.50 × 10.sup.-7                                                               1.07 × 10.sup.-7                         25               25.2   23.4   18.6                               4     324   --CO.sub.2 H.sup.a                                                                   37,102                                                                             0.97 8.79 × 10.sup.-7                                                               6.01 × 10.sup.-7                                                               6.87 × 10.sup.-7                         27               22.6   33.1   28.9                               5     972   --CO.sub.2 H.sup.a                                                                   111,373                                                                            0.34 7.83 × 10.sup.-7                                                               5.35 × 10.sup.-7                                                               6.17 × 10.sup.-7                         29               25.4   37.1   32.3                               __________________________________________________________________________     .sup.a Solution pH ranged 3.16-3.64, 7.01-7.04, and 13.24-13.33 for the       acidic, neutral, and basic solutions, respectively.                           .sup.b Solution pH ranged 2.28-4.74, 6.89-7.44, and 12.18-13.18 for the       acidic, neutral, and basic solutions, respectively.                           .sup.c Solution pH ranged 2.60-3.77, 7.04-7.10, and 12.10-12.69 for the       acidic, neutral, and basic solutions, respectively.                      

Unlike their acid-terminated parents, the alcohol-terminated cascadesexhibited no appreciable pH dependence of their hydrodynamic radii. Incontrast, the amine terminated polyamides exhibited a pH size dependencethat is approximately equal, but opposite to, that displayed by thecorresponding polyacids. The amines are "expanded" at acidic pH and"contracted" at basic pH, while the corresponding acids are largest("expanded") at neutral pH and smallest ("contracted") at acidic pH(FIG. 10). Remarkably, the third generational 108-acid and 108-amineeach undergo a maximum 35% change in hydrodynamic radius.

The branched amines 2,3, and 4 were used to prepare water-solublecascade polymers, possessing identical internal hierarchicalarchitectures, but with either acidic, neutral or basic terminalfunctional groups. The availability of these complementary seriesallowed an initial examination of the dependence of macro-molecularproperties on the nature of the cascade terminal group. The PFG NMRresults are consistent with the supposition that size variations arisefrom columbic repulsions between charged terminal moieties, which areformed as a function of pH. These findings should be general in thatdendritic macromolecules with other internal branching architectures andfunctional group linkages should also in a similar manner provided theirinterior branches are relatively flexible. As a consequence, the use ofcascade polymers as size standards in aqueous solution must be temperedby this pronounced pH dependence.

I. Experimental Synthesis

General Comments. Melting point data were obtained in capillary tubeswith a Gallenkamp melting point apparatus and are uncorrected. ¹ H and¹³ C NMR spectra were obtained in CDCl₃, except where noted, with Me₄ Sias the internal standard (δ=0 ppm), and recorded at 360 MHz. Infraredspectra (IR) were obtained (KBr pellet, unless otherwise noted) andrecorded in a Perkin-Elmer 621 grating infrared spectrometer. Massspectral (MS) data were obtained by Burt Wolf (FSU) at 79 eV on aFinnigan 4510 GC-mass spectrometer and are reported as (assignment,relative intensity). Elemental analyses were performed by M-H-WLaboratories, Phoenix, Ariz.

Dialysis: Purification of the water soluble acid, alcohol, and amineterminated cascade polymers with molecular weights greater than 1000 wasaccomplished via dialysis (H₂ O, 4 L, 12 h) using Spectra/Por® 6molecularporous dialysis membranes (1000 MWCO). In a typical procedurefor the cascade polyacids, five grams of crude polyacid were dissolvedin water (50 mL) using 10% NaOH to assist in the dissolution. Additionalbase was added resulting in a yellow colored solution at approximatelypH=7. The solution was poured in the appropriate length of dialysismembrane so that upon sealing the membrane tube was flaccid. The filledmembrane was dialyzed against four liters of stirred deionized water fortwelve hours, with replacement of the water at least once during thattime. During dialysis, the solution changed from a deep to pale yellowcolor, an insoluble white suspension appeared in the solution, and themembrane tube became rigid. The contents of the tube were filtered andthe water was removed in vacuo to provide the polysodiocarboxylatecascade as a white solid.

The alcohol cascades were dissolved in deionized water with no pHadjustment. The crude amine formate salts were dissolved in 2% HCl andeach resulting solution was poured into a dialysis membrane, which wassealed and placed in water as quickly as possible to minimizedegradation of the cellulose tubing that may occur under these acidicconditions.

Preparative HPLC: Small portions of the polyacids were subjected topreparative scale HPLC using an Isco Model 2350HPLC Pump, Isco Model2361 Gradient Programmer, Isco V⁴ ® Absorbance Detector, Spectra-PhysicsSP-4600 Integrator, Cygnet® Fraction Collector, and a DuPont Zorbax® ODS(C₁₈ -Octyldodecyl Sulfate, 21.2 m×25 cm) column. The dialyzed polyacidwas dissolved in water (ca. 75 mg/mL), titrated with 10% HCl to pH 3-4,and filtered through a 0.02 micron Anotop® alumina matrix filter beforeinjection (2 mL). The gradient conditions were 2 min. water followed bya 15 min. linear ramp to 60/40H₂ O/CH₃ CN. The retention time for theproduct was approximately 10 min at a flow rate of 20 mL/min, whichcorresponded to an operating pressure of 1,400 psi.

1,7-Diamino-4-(3-aminopropyl)-4-nitroheptane (6) was prepared aspreviously reported.⁵¹

1,7-Di-[N-tert-butoxycarbonyl)amino]-4-[3-(N-tert-butoxycarbonyl)-aminopropyl]-4-nitroheptane(7).

A mixture of triamine 6 (4.06 g, 17.5 mmol), Et₃ N (5.56 g, 54.9retool), and di-tert-butyl dicarbonate (12.00 g, 55.0 mmol) in MeOH (60mL) was refluxed for 2 hours before the solvent was removed in vacuo.The resulting residue was column chromatographed (SiO₂) eluting with 10%MeOH in EtOAc to provide (87%) tricarbamate 7, as a slightly hygroscopicwhite solid: 8.05 g; mp 48°-51° C.; ¹ H NMR δ1.44 (s, CH₃ and CH₂ CH₂CH₂, 33H), 1.90 (t, J=7.2Hz ⁴° CCH₂, 6H), 3.10 (t, J=5.0Hz CH₂ NH, 6H),4.72 (br, NH, 3H); ¹³ C NMR δ24.2 (CH₂ CH₂ CH₂), 28.3 (CH₃), 32.6 (⁴°CCH₂), 40.1 (CH₂ NH), 79.1 (CMe₃), 94.2 (⁴° CHO₂), 156.0 (CO); IR 3358(NH), 1687 (C═O), 1543 (NO₂), 1172 (C--O) cm⁻¹. Anal. Calcd for C₂₅ H₄₈N₄ O₈ : C, 56.37; H, 9.08; N, 10.52. Found: C, 56.76; H, 8.84; N, 10.50.MS m/e 533.2 (M⁺ +1,26).

1,7-Di-[N-tert-butoxycarbonyl)amino]-4-[3-(N-tert-butoxycarbonyl)aminopropyl]-4-aminoheptane (4).

A slurry of nitro tricarbamate 7 (8.06 g, 15.1 mmol), T-1 Raney Ni (10g), and absolute EtOH (300 mL) was hydrogenated at 55 psi and 60° C. for12 hours. The solution was cautiously filtered through Celite, to removethe catalyst, and the solvent removed in vacuo to give (92%) the aminotricarbamate 4, as a hygroscopic white solid: 7.60 g; ¹ H NMR δ1.33 (m,CH₂ CH₂ CH₂, 6H), 1.44 (s, CH₃ and ⁴° CCH₂, 33H), 3.10 (br, CH₂ NH, 6H),4.77 (br CONH, 3H); ¹³ C NMR δ24.1 (CH₂ CH₂ CH₂), 28.3 (CH₃), 36.9 (⁴°CCH₂), 40.9 (CH₂ NH), 52.8 (⁴° CNH₂), 79.0(CMe₃), 155.9 (CO); IR (neat)3355 (NH₂, NH), 1694 (C═O), 1170 (C--O) cm⁻¹. Anal. Calcd for C₂₅ H₅₀ N₄O₆ : C, 59.73; H, 10.02; N, 11.14. Found: C, 59,63; H, 9.85; N, 10.95.MS m/e 503.03 (M⁺ +1,25).

12-Cascade:methane[4]:(3-oxo-6-oxa-2-azaheptylidyne):tert-butylpropanoate (10)

General Procedure A.

A mixture of tetraacid 1 (9.73 g, 23 mmol), amine 2 (40.00 g, 96 mmol),dicyclohexylcarbodiimide (DCC: 19.80 g, 96 mmol), and1-hydroxybenzotriazole (1-HBT: 13.00 g, 96 mmol) in DMF (350 mL) wasstirred at 25° C. for 24 hours. After filtration to removedicyclohexylurea, the solvent was evaporated in vacuo to give a residue,which was dissolved in EtOAc (200 mL), then sequentially washed withcold aqueous HCl (10%), water, aqueous NaHCO₃ (10%), and brine. Theorganic phase was dried (MgSO₄), concentrated in vacuo, andchromatographed (SiO₂ column) eluting with 10% EtOAc in CH₂ Cl₂ tofurnish (70%) the desired 12-cascade ester 10, as a spongy white solid:32.33 g; mp 68°-72° C.; ¹ H NMR δ1.43 (s, CH₃, 108H), 1.96)t, J=7.2Hz,CH₂ CH₂ COO, 24H), 2.22 (t, J=7.2 Hz, CH₂ COO, 24H), 2.38 (t, J=5.7Hz,CH₂ CONH, 8H), 3.34 (s, CH₂ O, 8H), 3.67 (t, J=5.7 Hz, OCH₂, 8H), 6.38(s , NH, 4H); ¹³ C NMR δ28.1 (CH₃), 29.7 (CH₂ CH₂ COO), 37.4 (CH₂ COHN),45.4 (⁴° C_(Core)), 57.3 (⁴° CNH), 67.7 (CH₂ O), 68.9 (OCH₂), 80.4(CMe₃), 170.7 (CONH), 172.7 (CO₂); IR 3310 (NH), 1733 (ester C² O), 1664(amide C═O), 1157 (ester C--O)cm⁻¹. Anal. Calcd for C₁₀₅ H₁₈₄ N₄ O₃₂ ;C, 62.60; N, 9.20; N, 2.78. Found: C, 62.82; H, 9.14; N, 2.91.

12-Cascade: methane[4]:(3-oxo-6-oxa-2- azaheptylidyne):propanoic acid(11)

General Procedure B.

A solution of dodecaester 10 (30.00 g, 15 mmol) in 95% formic acid (100mL) was stirred at 25° C. for 12 hours. After concentration, toluene (50mL) was added and the solution was again evaporated in vacuo toazeotropically remove residual formic acid. The crude solid wasdissolved in a water (200 mL)/acetone (10 mL) mixture and thensequentially washed with CH₂ Cl₂ (50 mL) and EtOAc (50 mL). The aqueousphase was boiled with activated charcoal (0.5 g), filtered throughCelite, and then concentrated in vacuo to furnish the acid as a whitesolid, which was purified via dialysis and preparative reverse-phaseHPLC to give (72%) dodecaacid 11, as a white solid: 14.38 g; mp 64°-66°C.; ¹ H NMR (D₂ O/p-dioxane/3.54 ppm) δ1.76 (t, J=7.5Hz, CH₂ CH₂ COO,24H), 2.04 (t, J=7.5Hz, CH₂ COO, 24H), 2.24 (br, CH₂ CONH, 8H), 3.15(br, CH₂ O, 8H), 3.44 (br. OCH₂, 8H; ¹³ C NMR (D₂ O/p-dioxane/66.4 ppm)δ29.7 (CH₂ CH₂ COO), 30.1 (CH₂ COO), 37.0 (CH₂ CONH), 45.0 (⁴°C_(Core)), 57.8 (⁴° CNH), 67.6 (CH₂ O), 69.8 (OCH₂), 173.0 (CONH), 179.2(CO₂ H); IR 3366 (br, acid OH), 1720 (acid C═O), 1645 (amide C═O) cm⁻¹.Anal. Calcd for C₅₇ H₈₈ N₄ O₃₂ ; C, 51.04; H, 6.61; N, 4.18. Found: C,50.89; H, 6.83; N, 4.38.

36-Cascade:methane[4]:(3-oxo-6-oxa-2-azaheptylidyne):(3-oxo-2-azapentylidyne):tert-butylpropanoate (16) was prepared (57%), as a spongy white solid, fromdodecaacid 11 (5.63 g, 4.2 mmol), amine 2 (21.98 g, 52.9 mmol), DCC(10.89 g, 52.9 mmol) 1-HBT (7.14 g, 52.9 mmol), and DMF (250 mL) viaProcedure A: 14.55 g; mp 67°-70° C.; ¹ H NMR δ1.42 (s, CH₃, 324H), 1.95,2.20 (m, CH₂ CH₂ CO, 192H), 2.37 (t, J=5.7Hz, OCH₂ CH₂ CO, 8H), 3.32 (s,CH₂ O, 8H), 3.66 (t, J=5.7 Hz, OCH₂, 8H), 6.36 (s, NH, 16H); ¹³ C NMRδ28.1 (CH₃), 29.7 (CH₂ CH₂ CO), 37.4 (OCH₂ CH₂ CO), 45.4 (⁴° C_(Core)),57.3 (⁴° CNH), 67.7 (CH₂ O), 68.9 (OCH₂), 80.4 (CMe₃), 170.7 (CONH),172.6 (CO₂); IR 3311 (NH), 1730 (ester C═O), 1661 (amide C═O), 1157,(ester C--O) cm⁻¹. Anal. Calcd for C₃₂₁ H₅₅₆ N₁₆ O₉₂ : C, 63.08; H,9.17; N, 3.67. Found: C, 63.18; H, 8.89; N. 3.79.

36-Cascade:methane[4]:(3-oxo-6-oxa-2-azaheptylidyne):(3-oxo-2-azapentylidyne):propanoicacid(17) was prepared (77%) by hydrolysis of 36-ester 16 (13.55 g, 2.22mmol) via Procedure B: 6.95 g; mp 132°-134° C.; ¹ H NMR (5%NaOD/p-dioxane/3.54 ppm) δ1.75, 1.99 (br, CH₂ CH₂ CO, 192H), 2.32 (br,OCH₂ CH₂ CO, 8H), 3.19 (br, CH₂ O, 8H), 3.48 (br, OCH₂, 8H); ¹³ C NMR(5% NaOD/p-dioxane/66.4 ppm) δ29.7, 30.1 (CH₂ CH₂ CO), 37.0 (OCH₂ CH₂CO), 45.0 (°C_(Core), 57.9, 58.1 (⁴° CNH), 67.7 (CH₂ O), 69.9 (OCH₂),173.1 (CONH), 179.7 (CO₂); IR 3363 (br, acid OH), 1718 (acid C═O), 1648(amide C═O) cm⁻¹. Anal. Calcd for C₁₇₇ H₂₆₈ N₁₆ O₉₂ : C, 51.95; H, 6.60;N, 5.48. Found: C, 51.74; H, 6.71; N, 5.30.

108-Cascade:methane[4]:(3-oxo-6-oxa-2-azaheptylidyne):(3-oxo-2-azapentylidyne)²:tert-butyl propanoate (22) was prepared (48%), as a spongy white solidfrom 36-acid 17 (2.63 g, 643 μmol), amine 2 (10.10 g, 24.3 mmol), DCC(5.00 g, 24.3 mmol), 1-HBT (3.28 g, 24.3 mmol), and DMF (150 mL) viaProcedure A: 5.68 g; mp 103°-108° C. ; ¹ H NMR δ1.43 (s, CH₃, 972H),1.95, 2.19 (br, CH₂, 624H); ³ C NMR δ28.1 (CH₃), 29,7 (CH₂ CH₂), 57.3(⁴° CNH), 80.3 (CMe₃), 170.8 (CONH), 172.7 (CO₂); IR 3366 (NH), 1730(ester C═O), 1645 (amide C═O), 1160 (ester C--O) cm⁻¹. Anal. Calcd forC₉₆₉ H₁,672 N.sub. 52 O₂₇₂ : C, 63.24; H, 9.16; N. 3.96. Found: C,63.06; H, 8.89; N, 4.23.

108-Cascade:methane[4]:(3-oxo-6-oxa-2-azaheptylidyne):(3-oxo-2-azapentylidyne)²:propanoic acid (23) was prepared (70%) by hydrolysis of 108-ester 22(5.68 g, 309 μmol) via Procedure B: 2.65 g; mp 136°-139° C.; ¹ H NMR (5%NaOD/p-dioxane/3.54 ppm) δ1.71, 1.92 (br, CH₂ CH₂ CO, 624H), 2.34 (br,OCH₂ CH₂ CO, 8H), 3.22 (br, CH₂ O, 8H), 3.48 (br, OCH₂, 8H); ¹³ C NMR(5% NaOD/p-dioxane/66.4 ppm) δ31.0, 31.4 (br, CH₂ CH₂ CO), 58.3 (br, ⁴°CNH), 174.8 (CONH), 181.8 (CO₂); IR 3361 (br, acid OH), 1718 (acid C═O),1647 (amide C═O) cm⁻¹. Anal. Calcd for C₅₃₇ H₈₀₈ N₅₂ O₂₇₂ : C, 52.25; H,6.60; N, 5.90. Found: C, 52.06; H, 6.71; N; 5.76.

324-Cascade:methane[4]:(3-oxo-6-oxa-2-azapheptylidyne):(3-oxo-2-azapentylidyne)³-tert-butyl propanoate (26) was prepared (42%), as a spongy white solid,from 108-acid 23 (5.39 g, 437 μmol), amine 2 (20.00 g, 48.1 mmol), DCC(9.91 g, 48.1 mmol), 1-HBT (6.50 g, 48.1 mmol), and DMF (250 mL) viaProcedure A: 10.20 g; mp 135°-141° C.; ¹ H NMR δ1.39 (s, CH₃, 2916H),1.93-2.17 (m, CH₂, 1920H) ; ¹³ C NMR δ28.1 (CH₃), 29.6 (CH₂ CH₂), 57.2(⁴° CNH), 80.1 (CMe₃), 170.8 (CONH), 172.6 (CO₂ ; IR 3368 (NH), 1728(ester C═O), 1658 (amide C═O), 1160 (ester C--O) cm⁻¹. Anal. Calcd forC₂₉₁₃ H₅₀₂₀ N₁₆₀ O₈₁₂ : C, 63.29; H, 9.15; N, 4.05. Found: C, 63.47; H,8.99; N, 4.16.

324-Cascade:methane[4]:(3-oxo-6-oxa-2-azaheptylidyne):(3-oxo-2-azapentylidyne)³:propanoic acid (27) was prepared (72%), as a white solid by hydrolysisof 324-ester 26 (5.00 g, 90.4 μmol) via Procedure B: 2.42 g; mp138°-142° C.; ¹ H NMR (5% NaOD/p-dioxane/3.54 ppm) δ1.71-1.93 (br, CH₂CH₂ CO, 1920H), 2.38 (br, OCH₂ CH₂, 8H), 3.22 (br, CH₂ O, 8H), 3.48 (br,OCH₂, 8H); ¹³ C NMR (5% NaOd/p-dioxane/66.4 ppm) δ29.7, 30.8 (br, CH₂CH₂ CO), 57.4 (⁴° CNH), 174.3 (CONH), 182.0 (CO₂ H); IR 3361 (br, acidOH), 1720 (acid C═O), 1648 (amide C═O) cm⁻¹. Anal. Calcd for C₁₆₁₇ H₂₄₂₈N₁₆₀ O₈₁₂ : C, 52.35; H, 6.60; N, 6.04. Found: C, 52.42; H, 6.60; N,6.05.

972-Cascade:methane[4]:(3-oxo-6-oxa-2-azaheptylidyne):(3-oxo-2-azapentylidyne)⁴:tert-butyl propanoate (28) was prepared (45%), as a spongy white solid,from 324-acid 27 (5.40 g, 146 μmol), amine 2 (20.00 g, 48.1 mmol), DCC(9.91 g, 48.1 mmol), 1-HBT (6.50 g, 48.1 mmol), and DMF (250 mL) viaProcedure A: 10.87 g; mp 138°-142 ° C.; ¹ H NMR δ1.39 (s, CH₃, 8748H),1.93-2.17 (m, CH₂, 5808H); ¹³ C NMR δ28.0 (CH₃), 29.5 (CH₂ CH₂, 57.4 (⁴°CNH), 80.4 (CMe₃), 170.4 (CO₂), 172.6 (CONH); IR 3310 (NH), 1730 (esterC═O), 1645 (amide C═O), 1155 ester C--O) cm⁻¹. Anal. Calcd for C₈₇₄₅H₁₅₀₆₄ N₄₈₄ O.sub. 2432 :C, 63.31; H, 9.15; N, 4.09. Found: C, 63.47; H,9.31; N, 4.04.

972-Cascade:methane[4]:(3-oxo-6-oxa-2-azaheptylidnye):(3-oxo-2-azapentylidyne)⁴:propanoic acid was prepared (68%), as a white solid, by hydrolysis of972-ester 28 (9.50 g, 57.3 μmol) via Procedure B: 4.34 g; mp 144°-149°C.; ¹ H NMR (5% NaOD/p-dioxane/3.54 ppm) δ1.38-3.50 (br, CH₂ CH₂); ¹³ CNMR (5% DaOD/p-dioxane/66.4 ppm) δ28.4, 29.5 (CH₂ CH₂ CO₂ H), 56.5 (⁴°CNH), 172.3 (CONH), 174.8 (CO₂); IR 3419 (br, acid OH), 1718 (acid C═O),1638 (amide C═O) cm⁻¹. Anal. Calcd for C₄₈₅₇ H₇₂₈₈ N₄₈₄ O₂₄₃₂ : C,52.38; H. 6.60; N, 6.09. Found C, 52.24; H, 6.70; N, 6.03.

12-Cascade:methane[4]:(3-oxo-6-oxa-2-azaheptylidyne):1-acetoxypropane(8)

General Procedure C.

A mixture of tetraacid 1 (433 mg, 1.02 mmol), 1HBT (562 mg. 4.16 mmol),and DCC (858 mg, 4.16 mmol) in DMF (20 mL) was stirred at 0° C. for 1hour. Amine 3 (1.38 g, 4.16 mmol) in DMF (10 mL) was added to themixture, which was then stirred at 25° C. for an additional 23 hours.After filtration of dicyclohexylurea, the solvent was removed in vacuoto give an oily residue, which was column chromatographed (SiO₂) elutingwith MeOH/EtOAc (5:95) to give 47%) dodecaester 8 as a fruity-smelling,hygroscopic, waxy, white solid: 811 mg; ¹ H NMR δ1.57 (m, CH₂ CH₂ CO,24H), 1.74 (t, J=7.3Hz, ⁴° CNHCH₂, 24H), 2.05 (s, CH₃, 36H), 2.37 (t,J=5.8Hz, CH₂ CONH, 8H), 3.31 (s, ⁴° C_(Core) CH₂ O 8H), 3.63 (t,J=5.8Hz, OCH₂ CH₂, 8H), 4.04 (t, J=6.3Hz CH₂ OAc, 24H), 5.92 (s, NH,4H); ¹³ C NMR δ20.9 (CH₂ CH₂ CH₂ ), 22.6 (⁴° CNHCH₂), 31.0 (CH₃, 37.5(CH₂ CONH), 45.4 (⁴° C_(Core)), 57.8 (⁴° CNH), 64.4 (CH₂ OAc), 67.7 (⁴°C_(Core) CH₂), 67.7 (⁴° C_(Core) CH₂), 69,2 OCH₂ CH₂ CONH, 170.3 (CONH),171.0 (COO); IR (neat) 3397 (NH), 738 (ester C═O), 1643 (amide C═O),1245 (ester C--O) cm⁻¹. Anal. Calcd for C₈₁ H₁₃₆ N₄ O₃₂ : C, 57.98; H,8.17; N, 3.34. Found: C, 58.06; H, 8.35; N, 3.37.

12-Cascade:methane[4]:(3-oxo-6-oxa-2-azaheptylidnye:propanol (9)

General Procedure D.

A stirred slurry of dodecaester 8 (600 mg, 358 mmol), and K₂ CO₃ (100mg, 723 mmol) in absolute EtOH was refluxed. After 12 hours, thesolution was filtered and the solvent removed in vacuo to give aresidue, which was dissolved in water (20 mL) and dialyzed (H₂ O, 4 L,12 h) using a 1,000 MWCO Spectra/Pro® 6 molecularporous membrane.Removal of the water in vacuo gave (36%) dodecaalcohol 9 as a clear,colorless, waxy solid: 149 mg; ¹ H NMR (D₂ O/p-dioxane/3.54 ppm) δ1.29(br, CH₂ CH₂ CH₂, 24H), 1.51 (br, ⁴° CNHCH₂, 2.26 (br, CH₂ CONH, 8H),3.20 (s, ⁴° C_(Core) CH₂, 8H), 3.44 (br, CH₂ OAc, 24H), 3.48 (br, OCH₂CH₂ CONH, 8 H); ¹³ C NMR (D₂ O/p-dioxane/66.4 ppm) δ25.4 (CH₂ CH₂ CH₂),30.6 (⁴° CNHCH₂), 36.9 (CH₂ CONH), 45.1 (⁴° CNH), 61.9 (CH₂ OAc), 67.7(⁴° C_(Core) CH₂), 69.4 (OCH₂ CH₂ CONH), 172.8 CONH); IR (neat) 3343(OH), 1648 (amide C═O), 1059 (C--O) cm⁻¹. Anal. Calcd for C₅₇ H₁₁₂ N₄O₂₀ ; C, 58.34; H, 9.62; N, 4.77. Found: C, 58.39; H, 9.54; N, 4.59.

36-Cascade:methane[4]:(3-oxo-6-oxa-2-azaheptylidyne):(3-oxo-2-azapentylidyne):3-acetoxypropane(14) was prepared (50%), as a fruity-smelling, hygroscopic, waxy, whitesolid, from dodecaacid 11 (456 mg, 340 μmol), amine 3 (1.38 g, 4.16mmol), DCC (858 mg, 4.16 mmol), 1-HBT (562 mg, 4.16 mmol), and DMF (30mL) via Procedure C: 867 mg; ¹ H NMR δ1.52 (br, CH₂ CH₂ CH₂, 72H), 1.68(br, CH₂ CH₂ CH₂, 72H) 1.91, 2.19 (br, ⁴° CNHCH₂ CH₂ CONH, 48H ), 2.02(s, CH₃ , 108H), 2.34 (br, OCH₂ CH₂ CONH, 8H), 3.28 (s, ⁴ C_(Core) CH₂O, 8H), 3.58 (br, OCH₂ CH₂, 8H), 4.00 (t, J=6.2Hz, CH₂ OAc, 72H) ; ¹³ CNMR δ20.9 (CH₂ CH₂ CH₂), 22.5 (⁴° CNHCH₂), 30.9 (CH₃), 31.4 (⁴° CNHCH₂CH₂ CONH), 37.4 (OCH₂ CH₂ CONH ), 45.1 (⁴° C_(Core)), 57.7, 57.8 (⁴°CNH), 64.4 (CH₂ OAc), 67.8 (⁴° C_(Core) CH₂), 69.4 (OCH₂ CH₂ CONH),171.4 (COO), 172.6 (CONH); IR (neat) 3376 (NH), 1738 (ester C═O), 1658(amide C═O), 1247 (ester C--O) cm⁻¹. Anal. Calcd for C₂₄₉ H₄₁₉ N₁₆ O₉₂ ;C, 58.62; H, 8.14; N, 4.39. Found. C, 58.53; H, 8.33; N, 4.49.

36-Cascade:methane[4]:(3-oxo-6-oxa-2-azaheptylidyne):(3-oxo-2-azapentylidyne):propanol(15) was prepared (72%), as a hygroscopic white solid, from 36-ester 14(700 mg, 137 μmol) via Procedure D: 492 mg; mp 58°-60° C.; ¹ H NMR (D₂O/p-dioxane/3.54 ppm) δ1.25 (br, CH₂ CH₂ CH₂, 72H), 1.48 (br, CH₂ CH₂CH₂, 72H), 1.72 (br, ⁴° CNHCH₂ CH₂ CONH, 24H), 1.95 (br, ⁴° CNHCH₂ CH₂CONH, 24H), 2.27 (br, OCH₂ CH₂ CONH, 8H), 3.16 (br, ⁴° C_(Core) CH₂,8H), 3.36 (br, CH₂ OH, 72H), 3.46 (br, OCH₂ CH₂ CONH, 8H); ¹³ C NMR (D₂O/p-dioxane/66.4 ppm) δ25.3 (CH₂ CH₂ CH₂), 30.4 (CH₂ CH₂ CH₂), 30.8 (⁴°CNHCH₂ CH₂ CONH), 36.7 (OCH₂ CH₂ CONH), 45.0 (⁴° C_(Core)), 57.8, 58.4(⁴° CNH), 61.8 (CH₂ OH), 67.8 (⁴° C_(Core) CH₂), 69.2 (OCH₂ CH₂ CONH),174.5 (CONH); IR 3394 (OH), 1651 (amide C═O), 1059 (C--O) cm⁻¹. AnalCalcd for C₁₇₇ H₃₄₀ N₁₆ O₅₆ : C, 59.24; H, 9.55; N, 6.24. Found. C,59.54; H, 9.38; N, 5.99.

108-Cascade:methane[4]:)3-oxo-6-oxa-2-azaheptylidyne):3-oxo-2-azapentylidyne)²:1-acetoxypropane (20) was prepared (69%), as a fruity-smelling,hygroscopic, waxy, white solid, from 36-acid 17 (405 mg, 99.0 μmol),amine 3 (1.24 g, 3.74 mmol), DCC (771 mg, 3.74 mmol), 1-HBT (505 mg,3.74 mmol), and DMF (30 mL) via Procedure C: 1.05 g; ¹ H NMR δ1.56 (br,CH₂ CH₂ CH₂, 216H), 1.72 (br, CH₂ CH₂ CH₂, 216H), 2.05 (s, CH₃, 324H),4.03 (br, CH₂ OAc, 216H) ; ¹³ C NMR δ20.9 (CH₂ CH₂ CH₂), 22.5 (⁴°CNHCH₂), 30.8 (CH₃), 31.4 (⁴° CNHCH₂ CH₂ CONH), 37.4 (OCH₂ CH₂ CONH),57.8 (⁴° CNH), 64.5 (CH₂ OAc), 67.8 (⁴° C_(Core) CH₂), 69.4 (OCH₂ CH₂CONH), 171.1 (COO), 172.5 (CONH); IR (neat) 3376 (OH), 1738 (ester C═O),1661 (amide C═O), 1244 (ester C--O) cm⁻¹. Anal. Calcd for C₇₅₃ H₁₂₄₀ N₅₂O₂₇₂ : C, 58.83; H, 8.13; N, 4.74. Found: C, 58.81; H, 8.24; N, 4.51.

108-Cascade;methane[4]:(3-oxo-6-oxa-2-azaheptylidyne):3-oxo-2-azapentylidyne)²:propanol (21) was prepared (71%), as a hygroscopic white solid, from108-ester 20 (750 mg, 48.8 μmol) via Procedure D: 374 mg; mp 71°-76° C.;¹ H NMR (D₂ /O/p-dioxane/3.54 ppm) δ1.27 (br, CH₂ CH₂ CH₂, 216H), 1.49(br, CH₂ CH₂ CH₂, 216H), 1.70 (br, ⁴° CNHCH₂ CH₂ CONH, 96H), 1.96 (br,⁴° CNHCH₂ CH₂ CONH, 96H), 2.31 (br, OCH₂ CH₂ CONH, 8H), 3.20 (br, ⁴°C_(Core) CH₂, 8H), 3.38 (br, Ch₂ OH, 216H), 3.49 (br, OCH₂ CH₂ CONH,8H); ¹³ C NMR (D₂ O/p-dioxane/66.4 ppm) δ25.3 (CH₂ CH₂ CH₂ ), 30.4 (CH₂CH₂ CH₂) (30.8 (⁴° CNHCH₂ CH₂ CONH), 36.7 (OCH₂ CH₂ CONH), 57.8, 57.7(⁴° CNH), 61.8 (CH₂ OH), 67.8 (⁴° C_(Core) CH₂), 69.2 (OCH₂ CH₂ CONH),174.6 (CONH); IR 3343 (OH), 1653 (amide C═O), 1059 (C--O) cm⁻¹. Anal.Calcd for C₅₃₇ H₁₀₂₄ N₅₂ O₁₆₄ : C, 59.53; H, 9.53; N, 6.72. Found: C,59.37; H, 9.43; N, 6.79.

12-Cascade:methane[4]:(3-oxo-6-oxa-2-azaheptylidyne):N-tert-butoxycarbonyl)propylamine(12)

General Procedure E.

A mixture of tetracid 1 (458 mg, 1.08 mmol), 1-HBT (612 mg, 4.53 mmol),and DCC (934 mg, 4.53 mmol) in DMF (20 mL) was stirred at 25° C. for 1hour. Amine 4 (2.28 g, 4.54 mmol) in DMF (10 mL) was added to themixture, which was stirred for 12 hours. Additional DCC (300 mg, 1.46mmol) was added and the mixture was stirred for another 12 hours. Afterfiltration of dicyclohexylurea, the solvent was removed in vacuo to givea residue, which was dissolved in EtOAc (50 mL), sequentially washedwith cold aqueous HCl (10%), water, sat'd NaHCO₃, and brine. The organicphase was dried (MgSO₄), concentrated in vacuo, and chromatographed(SiO₂) eluting with 10% MeOH in EtOAc to furnish (56%) dodecacarbamate12, as a spongy white solid: 1.43 g; mp 87°-89° C.; ¹ H NMR δ 1.41 (s,CH₃ and CH₂ CH₂ CH₂, 132H), 1.67 (br, HN⁴° CCH₂ 24H) 2.35 (br, OCH₂ CH₂,8H), 3.05 (br, CH₂ NHBoc, 24H), 3.33 (br, ⁴° CCH₂ O, 8H), 3.64 (br,OCH₂, 8H), 5.06 (s, NHBoc, 12H), 6.37 (very br, CONH, 4H); ¹³ C NMRδ23.6 (CH₂ CH₂ CH₂), 28.4 (CH₃), 32.2 (HN⁴° CCH₂, 37.5 (OCH₂ CH₂), 40.8(CH₂ NHBoc), 58.2 (⁴° CNH), 67.9 (⁴° CCH₂ O), 69.5 (OCH₂), 78.9 (CMe₃),156.1 (NHCOO), 170.8 (CONH); IR 3353 (NH), 1684 (C═O), 1456, (C--N),1175 (C--O) cm⁻¹. Anal. Calcd for C₁₁₇ H₂₂₀ N₁₆ O₃₂ : C, 59.47; H, 9.38;N, 9.48. Found: C, 59.36; H, 9.23; N, 9.30.

12-Cascade:methane[4]:(3-oxo-6-oxa-2-azaheptylidyne):propylamineHydrochloride (13)

General Procedure F.

A solution of dodecacarbamate 12 (1.28 g, 542 μmol) in 95% formic acid(10 mL) was stirred at 25° C. for 12 hours. After concentrating invacuo, toluene (10 mL) was added and the solution was again evaporatedin vacuo to remove azeotropically any residual formic acid. The crudeformate salt was dissolved in aqueous 2% HCl (10%) and dialyzed (H₂ O, 1L, 12 h) using a 1,000 MWCO Spectra/Por® molecularporous membrane.Removal of the water in vacuo gave (37%) dodecaamine hydrochloride 13,as a hygroscopic, light yellow colored, glassy solid: 322 mg; ¹ H NMR(D₂ O/p-dioxane/3.54 ppm) δ1.43 (br, CH₂ CH₂ CH₂, 24H), 1.56 (br, NH⁴°CCH₂, 24H), 2.36 (br, CH₂ CONH, 8H), 2.81 (br, CH₂ NH₂, 24H), 3.20 (s,OCH₂, 8H), 3.48 (br, ⁴° C_(Core) CH₂ O, 8H); ¹³ C NMR δ20.7 (CH₂ CH₂CH₂), 30.8 (HN⁴° CCH₂) 36.4 (CH₂ CONH), 39.4 (CH₂ NH₂), 44.9 (C_(Core),58.0 ⁴° CNH), 67.8 (⁴° C_(Core) CH₂), 69.7 (OCH₂), 173.0 (CO); IR 3448(NH₃ ⁺) 2057 (NH₃ ⁺ overtone), 1648 (C═O) 1550 (NH₃ ⁺ bend) 1100 (C--NH₃⁺ 0 cm⁻¹.

36-Cascade:methane[4]:(3-oxo-oxa-2-azaheptylidyne):(3-oxo-2-azapentylidyne):N-(tert-butoxycarbonyl)propylamine(18) was prepared (68%), as a spongy white solid, from dodecaacid 11(483 mg, 360 μmol), amine 4 (2.28 g, 4.54 mmol), 1-HBT (612 mg, 4.54mmol), DCC (934 mg/300 mg, 4.54 mmol/1.46 mmol), and DMF (30 mL) viaProcedure E: 1.76 g; mp 109°-112° C.; ¹ H NMR δ1.43 (s, CH₃ and CH₂ CH₂CH₂, 396H), 1.66 (br, CH₂ CH₂ CH₂, 72H), 1.94 (br, HN⁴° CCH₂ CH₂ CONH,24H), 2.15 (br, HN⁴° CCH₂ CH₂ CONH, 24H), 2.35 (br, OCH₂ CH₂, 8H), 3.05(br, CH₂ NHBoc, 72H), 3.29 (br, ⁴° C_(Core) CH₂ O, 8H), 3.63 (br, OCH₂,8H), 5.33 [very br, NHBoc, 28H (exchange)]; ¹³ C NMR δ23.7 (CH₂ CH₂CH₂), 28.5 (CH₃), 31.9 (br, HN⁴° CCH₂ CH₂ CONH), 32.2 (CH₂ CH₂ CH₂),37.6 (OCH₂ CH), 40.9 (CH₂ NHBoc), 58.1 (⁴° C_(Core) CH₂ O), 69.6 (OCH₂),78.0 (CMe₃), 156.2 (NHCOO), 171.1 (CONH); IR 3350 (NH), 1697 (C--O),1455 (C--N), 1172 (C--O) cm⁻¹. Anal. Calcd for C₃₅₇ H₆₆₄ N₅₂ O₉₂ : C,59.91; H, 9.35; N, 10.18. Found: C, 59.97; H, 9.19; N, 9.99.

36-Cascade:methane[4]:(3-oxo-6-oxa-2-azaheptylidyne):(3-oxo-2-azapentylidyne):propylaminehydrochloride (19) was prepared from (49%), as a hygroscopic, lightyellow colored, glassy solid, from 36-carbamate 18 (1.61 g, 225 μmol)via Procedure F: 530 mg; m; >182° C. (dec); ¹ H NMR (D₂ O/p-dioxane/3.54ppm) δ1.43 (br, CH₂ CH₂ CH₂, 72H), 1.57 (br, CH₂ CH₂ CH₂, 72H), 1.74(br, HN⁴° CCH₂ CH₂ CONH, 24H), 2.05 (br, HN⁴° CCH₂ CH₂ CONH, 24H), 2.37(br, OCH₂ CH₂, 8H), 2.81 (br, CH₂ NH₃ ⁻ ; 72H), 3.23 (br, ⁴° C_(Core)CH₂ O, 8H), 3.50 (br, OCH₂, 8H); ¹³ C NMR (D₂ O/p-dioxane/66.4 ppm)δ20.8 (CH₂ CH₂ CH₂), 30.8 (br, CH₂ CH₂ CH₂ and HN⁴ ° CH₂ CH₂ CONH), 36.5(OCH₂ CH₂), 39.6 (CH₂ NH₃ ⁺), 44.9 (4° C_(Core)), 58.1 (4° CNH), 67.9(⁴° C_(Core) CH₂ O), 69.6 (br, OCH₂), 173.1 (OCH₂ CH₂ CONH), 175.3(CONH); IR 3448 (NH₃ ⁺) 2054 (NH₃ ⁺ overtone), 1646 (C═O), 1548 (NH₃ ⁺bend), 1098 (C--NH₃ ⁺) cm⁻¹.

108-Cascade:methane[4]:(3-oxo-6-oxa-2-azaheptylidyne):(3-oxo-2-azapentylidyne)²:N-tert-butoxycarbonyl)proplyamine (24) was prepared (70%), as a spongywhite solid, from 36-acid 17 (491 mg, 120 μmol), amine 4 (2.28 g, 4.45mmol), 1-HBT (612 mg, 4.45 mmol), DCC (934 mg/300 mg, 4.53 mmol/1.46mmol), and DMF (30 mL) via Procedure E: 1.81 g; mp 119°-123° C.; ¹ H NMRδ1.43 (s, CH₃ and CH₂ CH₂ CH₂, 1188H), 1.66 (br, CH₂ CH₂ CH₂, 216H),3.06 (br, CH₂ NHBoc, 216H), 5.33 (very br, NHBoc, exchange); ¹³ C NMRδ23.7 (CH₂ CH₂ CH₂), 28.5 (CH₃, 31.9 (br, HN⁴° CCH₂ CH₂ CONH), 32.2 (CH₂CH₂ CH₂), 40.9 (CH₂ NHBoc), 58.1 (br, ⁴° CNH), 78.9 (CMe₃), 156.2(NHCOO), 173.0 (br, CONH), IR 3337 (NH), 1698 (C═O), 1455 (C--N), 1170(C--O) cm⁻¹. Anal. Calcd for C₁₀₇₇ H₁₉₉₆ N₁₆₀ O₂₇₂ : C, 60.05; H, 9.34;N, 10.40. Found: C, 60.11; H, 9.16; N. 10.32.

108-Cascade:methane[4]:(3-oxo-6-oxa-2-azaheptylidyne):(3-oxo-2-apentylidyne)²:propylamine hydrochloride (25) was prepared (53%), as a hygroscopic,light yellow colored, glassy solid, from 108-carbamate 24 (1.66 g, 77.1μmol) via Procedure F: 593 mg; mp>198° C. (dec); ¹ H NMR (D₂O/p-dioxane/3.54 ppm) δ1.44 (br, CH₂ CH₂ CH₂, 216H), 1.58 (br, CH₂ CH₂CH₂, 216H), 1.73 (br, HN⁴° CCH₂ CH₂ CONH, 96H), 2.05 (br, HN⁴° CCH₂ CH₂CONH, 96H), 2.38 (br, OCH₂ CH₂, 8H), 2.82 (br, CH₂ NH₃ ⁺, 216H), 3.21(br, ⁴° C_(Core) CH₂ O, 8H), 3.49 (br, OCH₂, 8H) ; ¹³ C NMR (D₂O/p-dioxane/66.4 ppm) δ20.8 (CH₂ CH₂ CH₂ ), 30.8 (br, CH₂ CH₂ CH₂ andHN⁴° CH₂ CH₂ CONH), 36.5 (OCH₂ CH₂), 39.6 (CH₂ NH₃ ⁺), 45.4 (br, ⁴°C_(Core)), 58.1 (br, ⁴° CNH), 68.0 (br ⁴° C_(Core) CH₂ O), 69.7 (br,OCH₂), 175.4 (CONH); IR 3438 (NH₃ ⁺), 2060 (NH₃ ⁺ overtone), 1646 (C═O),1545 (NH₃ ⁺ bend), 1103 (C--NH₃ ⁺) cm⁻¹.

The invention has been described in an illustrative manner, and it is tobe understood the terminology used is intended to be in the nature ofdescription rather than of limitation.

Obviously many modifications and variations of the present invention arepossible in light of the above teachings. Therefore, it is to beunderstood that within the scope of the appended claims, the inventionmay be practiced otherwise than as specifically described.

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What is claimed is:
 1. A method of manipulating a unimolecular micellein an environment wherein the micelle includes at least one core atomand arms which terminate with hydrodynamic reactive groups branchingfrom said core atom forming an outer surface of said micelle, saidmethod including the steps of reversibly changing the solubility of thehydrodynamic reactive groups on the outer surface of the micelle in theenvironment while reversibly extending the arms of the micelle to expandand contract the micelle.
 2. A method of claim 1 wherein said step ofincreasing the solubility is further defined as changing the environmentto increase the solubility of the outer surface of the micelle in theenvironment.
 3. A method of claim 2 wherein the outer surface of themicelle includes chemical group reactive to pH changes, said step ofchanging the environment is further defined as changing the pH of theenvironment.
 4. A method of claim 2 wherein said step of changing theenvironment is further defined as changing the hydrophilic/lipophilicproperties of the environment.
 5. A method of claim 1 wherein said stepof extending the arms is further characterized by modifying theflexibility of the arms of the micelles.
 6. A method of claim 5 whereinsaid step of modifying the flexibility of the arms is further defined asincorporating at least one carbon-carbon double bond into an arm of themicelle.
 7. A method of claim 5 wherein said modifying step is furtherdefined as incorporating onto the arms of the micelle a moiety selectedfrom the group consisting of complexed bipyridenes, phenanthrenes anddisubstituted benzene.
 8. A method of claim 1 further including thesteps of exposing internal void areas formed between the arms of themicelle during expansive of the micelle.
 9. A method of claim 1 whereinsaid expanding step is further defined as reversibly changing thehydrodynamic radius of the micelle.
 10. A method of claim 1 wherein thearms of the micelle include terminal groups exposed on the surface ofthe micelle to the environment, said changing step being further definedas modifying the hydrodynamic properties of the surface of the micelleby reversibly protonating and deprotonating the terminal groups.
 11. Amethod of claim 10 wherein the terminal groups are selected from thegroup consisting essentially of carboxyl, amines, alcohols, amines,carboxyls, thiols, phosphines, ammonium ions, sulfoniums ions,phosphonium ions, nitrates, sulfates, phosphates, and carboxylateswherein an effective number of the terminal groups are protonated in thechanging environment to effect the hydrodynamic change of the surface ofthe micelle to reversibly expand and contract the micelle.